Variant Annotation
Available parameters and response documentation is available here
GET /lookup/BRAF:V600E?add-AMP-annotation=1&sex=male&age=47
{ "chromosome": "chr7", "alt": "T", "ref": "A", "pos": 140453136, "variant_id": "10190071404531360004", "regions": { "uniprot_regions": { "version": "07-Nov-2025", "items": [ { "absolute_positon": 2611797646, "amino_acid": "M1-E46,V47-E80,A81-V168,V169-G203,G203-F237,V238-D287,D287-G327,G327-D380,D381-G393,G393-M438,K439-G478,G478-R506,R506-D565,D565-N581,N581-M620,A621-Q664,I665-Q709,I710-H766", "chromo": "chr7", "colour": "255,0,0", "description": null, "length": 194265, "position": 140430465, "protein": "BRAF_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 2611801728, "amino_acid": "I457-L717", "chromo": "chr7", "colour": "153,153,255", "description": "Protein kinase", "length": 46893, "position": 140434547, "protein": "BRAF_HUMAN", "type": "domain", "pub_med_references": null } ] }, "nih_gtex": { "version": "v10", "items": [ { "GTExJsonData": { "exon_id": "ENSG00000157764.14_21", "exon_number": "21", "expressions": { "adipose_subcutaneous": 0.18350000000000002, "adipose_visceral_omentum": 0.16930000000000003, "adrenal_gland": 0.08951000000000002, "artery_aorta": 0.1276, "artery_coronary": 0.1401, "artery_tibial": 0.1701, "bladder": 0.22700000000000004, "brain_amygdala": 0.04556000000000001, "brain_anterior_cingulate_cortex_ba24": 0.06465000000000001, "brain_caudate_basal_ganglia": 0.05686000000000001, "brain_cerebellar_hemisphere": 0.11320000000000002, "brain_cerebellum": 0.09920000000000004, "brain_cortex": 0.06385, "brain_frontal_cortex_ba9": 0.07999000000000002, "brain_hippocampus": 0.05304000000000001, "brain_hypothalamus": 0.05949000000000001, "brain_nucleus_accumbens_basal_ganglia": 0.05757000000000001, "brain_putamen_basal_ganglia": 0.04980000000000001, "brain_spinal_cord_cervical_c_1": 0.07343000000000001, "brain_substantia_nigra": 0.05396000000000001, "breast_mammary_tissue": 0.19020000000000004, "cells_cultured_fibroblasts": 0.2093, "cells_ebv_transformed_lymphocytes": 0.48800000000000004, "cervix_ectocervix": 0.18290000000000003, "cervix_endocervix": 0.1771, "colon_sigmoid": 0.14090000000000003, "colon_transverse": 0.11110000000000002, "esophagus_gastroesophageal_junction": 0.1265, "esophagus_mucosa": 0.14340000000000003, "esophagus_muscularis": 0.1318, "fallopian_tube": 0.1716, "heart_atrial_appendage": 0.12450000000000001, "heart_left_ventricle": 0.08103000000000002, "kidney_cortex": 0.1044, "kidney_medulla": 0.15280000000000002, "liver": 0.06417000000000002, "lung": 0.18190000000000003, "minor_salivary_gland": 0.13520000000000001, "muscle_skeletal": 0.11070000000000002, "nerve_tibial": 0.16550000000000004, "ovary": 0.15350000000000003, "pancreas": 0.08577000000000003, "pituitary": 0.11580000000000001, "prostate": 0.14700000000000002, "skin_not_sun_exposed_suprapubic": 0.19350000000000003, "skin_sun_exposed_lower_leg": 0.2033, "small_intestine_terminal_ileum": 0.11290000000000001, "spleen": 0.07961000000000001, "stomach": 0.10710000000000001, "testis": 0.6534000000000001, "thyroid": 0.18250000000000002, "uterus": 0.15630000000000002, "vagina": 0.16180000000000003, "whole_blood": 0.12990000000000002 }, "gencode_id": "ENSG00000157764", "gene": "BRAF", "gene_model_positions": { "chromosome": "chr7", "end": 140624729, "start": 140419127, "strand": "-" }, "gene_positions": { "chromosome": "chr7", "end": 140624729, "start": 140419127, "strand": "-" } }, "absolute_positon": 2611820257, "chromo": "chr7", "length": 118, "position": 140453076 } ] } }, "variant_type": "SNV", "cytobands": "7q34", "refseq_transcripts": [ { "items": [ { "name": "NM_001374258.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1919T>A", "hgvs_p1": "V640E", "hgvs_p3": "p.(Val640Glu)", "location": "exon 16 of 20 position 58 of 119", "coding_location": "640 of 808", "canonical": true, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": "ENST00000644969.2", "uniprot_id": null }, { "name": "NM_004333.6", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1799T>A", "hgvs_p1": "V600E", "hgvs_p3": "p.(Val600Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "600 of 767", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000646891.2", "mane_plus": null, "uniprot_id": null }, { "name": "NM_001354609.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1799T>A", "hgvs_p1": "V600E", "hgvs_p3": "p.(Val600Glu)", "location": "exon 15 of 19 position 58 of 119", "coding_location": "600 of 768", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001374244.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1919T>A", "hgvs_p1": "V640E", "hgvs_p3": "p.(Val640Glu)", "location": "exon 16 of 19 position 58 of 119", "coding_location": "640 of 807", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378467.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1808T>A", "hgvs_p1": "V603E", "hgvs_p3": "p.(Val603Glu)", "location": "exon 15 of 19 position 58 of 119", "coding_location": "603 of 771", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378468.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1799T>A", "hgvs_p1": "V600E", "hgvs_p3": "p.(Val600Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "600 of 759", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378469.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1733T>A", "hgvs_p1": "V578E", "hgvs_p3": "p.(Val578Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "578 of 745", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378470.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1697T>A", "hgvs_p1": "V566E", "hgvs_p3": "p.(Val566Glu)", "location": "exon 14 of 18 position 58 of 119", "coding_location": "566 of 734", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378471.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1688T>A", "hgvs_p1": "V563E", "hgvs_p3": "p.(Val563Glu)", "location": "exon 14 of 18 position 58 of 119", "coding_location": "563 of 731", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378472.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1643T>A", "hgvs_p1": "V548E", "hgvs_p3": "p.(Val548Glu)", "location": "exon 15 of 19 position 58 of 119", "coding_location": "548 of 716", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378473.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1643T>A", "hgvs_p1": "V548E", "hgvs_p3": "p.(Val548Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "548 of 715", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378474.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1799T>A", "hgvs_p1": "V600E", "hgvs_p3": "p.(Val600Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "600 of 712", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001378475.1", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1535T>A", "hgvs_p1": "V512E", "hgvs_p3": "p.(Val512Glu)", "location": "exon 14 of 18 position 58 of 119", "coding_location": "512 of 680", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "232" } ], "ensembl_transcripts": [ { "items": [ { "name": "ENST00000288602.6", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.1799T>A", "hgvs_p1": "V600E", "hgvs_p3": "p.(Val600Glu)", "location": "exon 15 of 18 position 58 of 119", "coding_location": "600 of 767", "canonical": true, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "P15056" }, { "name": "ENST00000479537.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 2 of 6 position 58 of 119", "coding_location": null, "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": "5", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000496384.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.620T>A", "hgvs_p1": "V207E", "hgvs_p3": "p.(Val207Glu)", "location": "exon 6 of 10 position 58 of 119", "coding_location": "207 of 375", "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": "5", "ensembl_appris": "alternative1", "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000497784.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 16 of 19 position 58 of 119", "coding_location": null, "canonical": false, "gene_symbol": "BRAF", "splice_distance": "58", "ensembl_support_level": "5", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "115" } ], "gnomad_exomes": [ { "version": "2.1.1", "filter": "PASS", "ac": 1, "an": 251260, "af": 3.979941096871766e-6, "ac_sas": 1, "ac_sas_male": 1, "ac_male": 1, "an_afr": 16252, "an_amr": 34528, "an_asj": 10076, "an_eas": 18392, "an_eas_kor": 3816, "an_eas_jpn": 152, "an_eas_oea": 14424, "an_fin": 21638, "an_nfe": 113638, "an_nfe_bgr": 2668, "an_nfe_est": 240, "an_nfe_nwe": 42154, "an_nfe_onf": 30954, "an_nfe_seu": 11496, "an_nfe_swe": 26126, "an_oth": 6124, "an_sas": 30612, "an_afr_male": 6182, "an_amr_male": 14282, "an_asj_male": 5176, "an_eas_male": 9066, "an_fin_male": 11274, "an_nfe_male": 63536, "an_oth_male": 3208, "an_sas_male": 23068, "an_afr_female": 10070, "an_amr_female": 20246, "an_asj_female": 4900, "an_eas_female": 9326, "an_fin_female": 10364, "an_nfe_female": 50102, "an_oth_female": 2916, "an_sas_female": 7544, "an_male": 135792, "an_female": 115468, "age_hist_het_70_75": 1, "variant_type": "multi-snv", "segdup": true, "main_data": "ƒ = 0.00000398" } ], "gnomad_exomes_coverage": [ { "version": "2.1", "coverage_mean": [ 82.52400207519531 ], "coverage_median": [ 85.0 ], "coverage_20_frequency": [ 0.9980925931577502 ] } ], "gnomad_genomes_coverage": [ { "version": "2.1", "coverage_mean": [ 30.645000457763672 ], "coverage_median": [ 30.0 ], "coverage_20_frequency": [ 0.9365215002899259 ] } ], "dann_snvs": [ { "version": "2014", "dann_score": 0.9848628192999054 } ], "ncbi_clinvar2": [ { "version": "07-Jan-2026", "review_status": "criteria provided, conflicting classifications", "review_stars": 1, "variation_id": 13961, "num_submitters": 21, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22039425, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 25950823, 28854169, 29925953, 31891627, 34476331 ], "clinical_significance": [ "Conflicting Classifications Of Pathogenicity" ], "last_evaluation": "20251227", "origin": null, "accessions": [ { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND RASopathy", "submissions": [ { "submitter_date": 20250207, "submission_description": [ "This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 600 of the BRAF protein (p.Val600Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported as a known somatic variant in various cancers but has not been reported in the literature in individuals affected with germline BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13961). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. This variant disrupts the p.Val600 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance." ], "review_description": "Uncertain significance", "submitter_name": "Labcorp Genetics (formerly Invitae), Labcorp", "review_date": 20250123, "diseases": [ { "symbols": { "medgen": "CN166718" } } ], "method": "clinical testing", "date_updated": 20250225, "origin": "germline", "clinical_significance": [ "Uncertain significance" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005812663" } ], "submission_description": [], "review_date": 20250123, "diseases": [ { "normalized_disease": [ "Rasopathy" ], "symbols": { "medgen": "C5555857", "mondo": "MONDO:0021060" }, "names": [ "Rasopathy", "Rasopathies", "Noonan Spectrum Disorder" ] } ], "date_created": 20250225, "clinical_significance": [ "Uncertain significance" ], "review_description": "Uncertain significance", "allele_id": 29000, "accession_id": "RCV005089260" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Vascular malformation", "submissions": [ { "submitter_date": 20231212, "submission_description": [ "The BRAF c.1799T>A (p.Val600Glu) variant was identified at an allelic fraction consistent with somatic origin. This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs in a highly conserved residue within the CR3 activation segment, amino acids 594-627, of BRAF that is defined as a critical functional domain (Wellbrock C, et al., PMID: 15520807; Gelb BD, et al., PMID: 29493581). The BRAF c.1799T>A (p.Val600Glu) variant in a somatic state has been reported in multiple individuals affected with sporadic vascular malformations, brain arteriovenous malformation (BAVM) and spinal arteriovenous malformation (SAVM) (Hong T, et al., PMID: 30544177; Al-Olabi L, et al., PMID: 29461977; Goss JA, et al., PMID: 31891627; Li H, et al., PMID: 34530633). The BRAF c.1799T>A (p.Val600Glu) variant has been reported in the ClinVar database as pathogenic by numerous submitters (ClinVar ID: 13961). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies show constitutively active kinase activity (Rodriguez-Viciana P, et al., PMID: 16439621; Sarkozy A, et al., PMID:19206169; Al-Olabi L, et al., PMID: 29461977). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Clinical Genomics Laboratory, Washington University in St. Louis", "review_date": 20231022, "diseases": [ { "normalized_disease": [ "Vascular Malformation" ], "names": [ "Vascular Malformation" ] } ], "method": "clinical testing", "date_updated": 20231224, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004176942" } ], "submission_description": [], "review_date": 20231022, "diseases": [ { "normalized_disease": [ "Vascular Malformation" ], "symbols": { "medgen": "C0158570", "mondo": "MONDO:0024291" }, "names": [ "Vascular Malformation", "Vascular Malformations" ] } ], "date_created": 20231224, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV003458334" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cardiovascular phenotype", "submissions": [ { "submitter_date": 20240424, "submission_description": [ "ASSESSED FOR SOMATIC SAMPLE ONLY. FOR ANY GERMLINE INDICATION, PLEASE REASSESS." ], "review_description": "Likely pathogenic", "submitter_name": "Ambry Genetics", "review_date": 20220523, "finding": [ { "symbols": { "medgen": "CN230736" } } ], "method": "clinical testing", "date_updated": 20240501, "origin": "germline", "clinical_significance": [ "Likely pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005022010" } ], "submission_description": [], "review_date": 20220523, "diseases": [ { "symbols": { "medgen": "CN230736" }, "names": [ "Cardiovascular Phenotype" ] } ], "date_created": 20240501, "clinical_significance": [ "Likely pathogenic" ], "review_description": "Likely pathogenic", "allele_id": 29000, "accession_id": "RCV004018627" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lymphangioma", "submissions": [ { "submitter_date": 20220325, "submission_description": [ "The Val600Glu variant in BRAF was observed at very low levels (VAF 0.3-2%) in lymphatic malformation tissue from three unrelated individuals using high depth NGS (VANseq), confirmatory digital droplet PCR, and BRAF V600E immunohistochemistry." ], "review_description": "Pathogenic", "submitter_name": "James Bennett Lab, Seattle Childrens Research Institute", "review_date": 20220209, "finding": [ { "symbols": { "hp": "HP:0100766" }, "normalized_phenotype": [ "Abnormal Lymphatic Vessel Morphology" ] } ], "diseases": [ { "symbols": { "hp": "HP:0100764" } } ], "method": "research", "date_updated": 20250803, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV002318371" } ], "submission_description": [], "review_date": 20220209, "diseases": [ { "normalized_disease": [ "Lymphangioma" ], "symbols": { "medgen": "C0024221", "mondo": "MONDO:0002013", "human_phenotype_ontology": "HP:0100764" }, "names": [ "Lymphangioma" ] } ], "date_created": 20220328, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV002051586" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Multiple myeloma", "submissions": [ { "submitter_date": 20190912, "submission_description": [], "review_description": "Likely pathogenic", "submitter_name": "Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center", "review_date": 20190831, "diseases": [ { "normalized_disease": [ "Plasma Cell Myeloma" ], "normalized_cancer": [ "Plasma Cell Myeloma" ], "symbols": { "orphanet": "ORPHA29073" }, "names": [ "Plasma Cell Myeloma" ] } ], "method": "clinical testing", "date_updated": 20191223, "origin": "somatic", "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001132084" } ], "submission_description": [], "review_date": 20190831, "diseases": [ { "normalized_cancer": [ "Plasma Cell Myeloma" ], "symbols": { "omim": "254500", "medgen": "C0026764", "orphanet": "85443", "mesh": "D009101", "mondo": "MONDO:0009693", "human_phenotype_ontology": "HP:0006775" }, "names": [ "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Multiple Myeloma, Somatic" ], "normalized_disease": [ "Plasma Cell Myeloma" ], "keyword": "Hereditary cancer syndrome" } ], "date_created": 20170308, "clinical_significance": [ "Likely pathogenic" ], "review_description": "Likely pathogenic", "allele_id": 29000, "accession_id": "RCV000430562" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nephroblastoma", "submissions": [ { "submitter_date": 20200116, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Pediatric Oncology, Johns Hopkins University", "review_date": 20190215, "diseases": [ { "normalized_disease": [ "Kidney Wilms Tumor" ], "normalized_cancer": [ "Wilms' Tumor" ], "names": [ "Kidney Wilms Tumor" ] } ], "method": "clinical testing", "date_updated": 20250413, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001147031" } ], "submission_description": [], "review_date": 20190215, "diseases": [ { "normalized_disease": [ "Kidney Wilms Tumor" ], "normalized_cancer": [ "Wilms' Tumor" ], "symbols": { "medgen": "C0027708", "mesh": "D009396", "mondo": "MONDO:0006058", "human_phenotype_ontology": "HP:0000115" }, "names": [ "Kidney Wilms Tumor", "Kidney Wilms Tumor", "Kidney Wilms Tumor" ] } ], "date_created": 20200719, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV001248834" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cystic epithelial invagination containing papillae lined by columnar epithelium", "submissions": [ { "submitter_date": 20171127, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20150507, "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "method": "literature only", "date_updated": 20180714, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000784606" }, { "submitter_date": 20220321, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "review_date": 20150507, "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV002106413" } ], "submission_description": [], "review_date": 20150507, "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "date_created": 20180714, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000662278" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Papillary thyroid carcinoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in thyroid gland papillary carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25417114, 12970315, 14508525, 21878896)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241218, "diseases": [ { "symbols": { "mondo": "MONDO:0005075" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105546" }, { "submitter_date": 20220317, "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_cancer": [ "Papillary Thyroid Cancer" ], "names": [ "Thyroid Carcinoma, Papillary, Somatic" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000035249" } ], "submission_description": [], "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "pub_med": [ 26389271, 26389258 ], "normalized_disease": [ "Thyroid Gland Papillary Carcinoma" ], "normalized_cancer": [ "Papillary Thyroid Cancer" ], "symbols": { "medgen": "C0238463", "orphanet": "146", "mesh": "D000077273", "mondo": "MONDO:0005075", "human_phenotype_ontology": "HP:0002895" }, "names": [ "Thyroid Gland Papillary Carcinoma", "Nonmedullary Thyroid Carcinoma, Papillary", "Thyroid Carcinoma, Papillary, Somatic", "Thyroid Gland Papillary Carcinoma" ] } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000014993" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Melanoma", "submissions": [ { "submitter_date": 20250226, "submission_description": [ "Vemurafenib and cobimetinib combination is an FDA approved first line treatment for BRAF V600E mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib)." ], "submitter_name": "Wagner Lab, Nationwide Children's Hospital", "review_date": 20181101, "diseases": [ { "normalized_disease": [ "Melanoma" ], "normalized_cancer": [ "Melanoma" ], "names": [ "Melanoma" ] } ], "method": "curation", "date_updated": 20250304, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV005870910" }, { "submitter_date": 20240216, "submission_description": [ "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy than with BRAF inhibitor alone." ], "submitter_name": "CIViC knowledgebase, Washington University School of Medicine", "review_date": 20180515, "diseases": [ { "normalized_disease": [ "Melanoma" ], "normalized_cancer": [ "Melanoma" ], "names": [ "Melanoma" ] } ], "method": "curation", "date_updated": 20240220, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV004565360" }, { "submitter_date": 20220317, "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_disease": [ "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ], "normalized_cancer": [ "MELANOMA, MALIGNANT, SOMATIC" ], "names": [ "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000035247" } ], "submission_description": [], "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "pub_med": [ 26389333, 26389258 ], "normalized_cancer": [ "Melanoma" ], "symbols": { "medgen": "C0025202", "mesh": "D008545", "mondo": "MONDO:0005105", "human_phenotype_ontology": "HP:0007474" }, "names": [ "Melanoma" ], "normalized_disease": [ "Melanoma" ], "keyword": "Neoplasm" } ], "date_created": 20131031, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000067669" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nongerminomatous germ cell tumor", "submissions": [ { "submitter_date": 20220317, "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_cancer": [ "NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC" ], "names": [ "Nonseminomatous Germ Cell Tumors, Somatic" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000043966" } ], "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_cancer": [ "Nongerminomatous germ cell tumor", "NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC", "Germ cell tumor, nonseminomatous", "Non-seminomatous germ-cell tumors" ], "symbols": { "medgen": "C1266158", "mondo": "MONDO:0021656" }, "names": [ "Nongerminomatous Germ Cell Tumor", "Nonseminomatous Germ Cell Tumors, Somatic", "Nongerminomatous Germ Cell Tumor", "Non-Seminomatous Germ-Cell Tumors" ], "normalized_disease": [ "Nongerminomatous Germ Cell Tumor" ], "keyword": "Neoplasm" } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000022677" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Astrocytoma, low-grade, somatic", "submissions": [ { "submitter_date": 20220317, "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_cancer": [ "ASTROCYTOMA, LOW-GRADE, SOMATIC" ], "names": [ "Astrocytoma, Low-Grade, Somatic" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000035250" } ], "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_cancer": [ "Astrocytoma, low-grade, somatic" ], "symbols": { "medgen": "C2674727" }, "names": [ "Astrocytoma, Low-Grade, Somatic" ] } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000014994" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Carcinoma of colon", "submissions": [ { "submitter_date": 20220317, "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "COLORECTAL CANCER, SOMATIC" ], "names": [ "Colorectal Cancer" ] } ], "method": "literature only", "date_updated": 20220328, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000035248" } ], "submission_description": [ "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.", "Malignant Melanoma", "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.", "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.", "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.", "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.", "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.", "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.", "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.", "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.", "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.", "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.", "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.", "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.", "Colorectal Carcinoma", "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.", "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.", "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.", "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.", "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.", "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).", "Papillary Thyroid Carcinoma", "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.", "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.", "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.", "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.", "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.", "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.", "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.", "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.", "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.", "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.", "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.", "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.", "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.", "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.", "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.", "Nonseminomatous Germ Cell Tumors", "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.", "Astrocytoma", "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.", "Role in Neurodegeneration", "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.", "Variant Function", "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.", "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation." ], "review_date": 20140904, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 22113612, 22281684, 23302800, 23685455, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "diseases": [ { "pub_med": [ 19042984, 25006736, 17060676, 22138009, 24996433, 22855150, 23012255, 25373533, 23852704, 23429431, 34043773 ], "normalized_cancer": [ "Bowel" ], "symbols": { "medgen": "C0699790", "mondo": "MONDO:0002032" }, "names": [ "Malignant Colon Neoplasm", "Malignant Colon Neoplasm", "Malignant Colon Neoplasm" ], "normalized_disease": [ "Malignant Colon Neoplasm" ], "keyword": "Hereditary cancer syndrome" } ], "date_created": 20130404, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000014992" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND not provided", "submissions": [ { "submitter_date": 20201126, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Clinical Genetics and Genomics, Karolinska University Hospital", "review_date": 20140711, "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20201212, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001450230" }, { "submitter_date": 20180919, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Eurofins Ntd Llc (ga)", "review_date": 20131008, "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20250413, "origin": "germline", "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000112810" }, { "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System", "submitter_date": 20210331, "submission_description": [], "review_description": "Uncertain significance", "diseases": [ { "names": [ "Not Provided" ] } ], "method": "clinical testing", "date_updated": 20210413, "origin": "unknown", "clinical_significance": [ "Uncertain significance" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001550994" }, { "submitter_name": "Sylvester Comprehensive Cancer Center, University of Miami", "submitter_date": 20211006, "submission_description": [ "BRAF V600E variant is involved in encoding cytoplasmic serine/threonine kinases within the MAPK pathway. The NCCN Guidelines state that BRAF mutations are an indicative prognostic marker with poor clinical outcome. It it recommended to do baseline genomic genotyping of the patient's primary or metastatic tumor tissue at diagnosis if the patient is stage IV. BRAF V600E is mutated in about 15% of all cancers (El-Osta et. al, 2011). Frequency of all RAF mutations is 2.2% within pancreatic cancer, where BRAF V600E is one of the more common variants, and is actionable (Hendifar et al., 2021)" ], "review_description": "Pathogenic", "diseases": [ { "symbols": { "medgen": "CN517202" } } ], "method": "clinical testing", "date_updated": 20250803, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001962698" } ], "submission_description": [], "review_date": 20140711, "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "date_created": 20140117, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000080903" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Non-small cell lung carcinoma", "submissions": [ { "submitter_date": 20190321, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20090529, "diseases": [ { "symbols": { "mesh": "D002289" } } ], "method": "clinical testing", "date_updated": 20150131, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000061601" } ], "submission_description": [], "review_date": 20090529, "diseases": [ { "pub_med": [ 24868098, 24673736, 24627688, 23667368, 30813707 ], "normalized_disease": [ "Non-Small Cell Lung Carcinoma" ], "normalized_cancer": [ "Non-Small Cell Lung Cancer" ], "symbols": { "medgen": "C0007131", "mesh": "D002289", "mondo": "MONDO:0005233", "human_phenotype_ontology": "HP:0030358" }, "names": [ "Non-Small Cell Lung Carcinoma", "Non-Small Cell Lung Carcinoma" ], "disease_mechanism": "Other" } ], "date_created": 20130503, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000037936" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Ganglioglioma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in ganglioglioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 34185076, 20156809, 21274720, 29880043, 32289278, 24238153)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241226, "diseases": [ { "symbols": { "mondo": "MONDO:0016733" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105544" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Ganglioglioma" ], "normalized_cancer": [ "Mixed cell tumors containing both neural ganglionic cells and neural glial cell components" ], "symbols": { "medgen": "C0206716", "mondo": "MONDO:0016733", "human_phenotype_ontology": "HP:0033664" }, "names": [ "Ganglioglioma", "Mixed Cell Tumors Containing Both Neural Ganglionic Cells Neural Glial Cell Components" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253603" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Pilocytic astrocytoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in pilocytic astrocytoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 23583981, 23817572, 32289278, 34718782)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241030, "diseases": [ { "symbols": { "mondo": "MONDO:0016691" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105549" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Pilocytic Astrocytoma" ], "normalized_cancer": [ "Pilocytic Astrocytoma" ], "symbols": { "medgen": "C0334583", "mondo": "MONDO:0016691", "human_phenotype_ontology": "HP:0033680" }, "names": [ "Pilocytic Astrocytoma", "Pilocytic Astrocytoma, Somatic" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253599" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Malignant glioma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in malignant glioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 23583981, 28912153, 28966033, 25752754, 23552385, 29763623)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250603, "diseases": [ { "symbols": { "mondo": "MONDO:0100342" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105131" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Malignant Glioma" ], "normalized_cancer": [ "Malignant glioma" ], "symbols": { "medgen": "C0555198", "mondo": "MONDO:0100342" }, "names": [ "Malignant Glioma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253604" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Diffuse midline glioma, H3 K27M-mutant", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20221226, "diseases": [ { "symbols": { "mondo": "MONDO:0957196" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105098" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Diffuse Midline Glioma, H3 K27M-Mutant" ], "normalized_cancer": [ "Diffuse Glioma" ], "symbols": { "medgen": "C4289688", "mondo": "MONDO:0957196" }, "names": [ "Diffuse Midline Glioma, H3 K27M-Mutant" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253605" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Malignant peripheral nerve sheath tumor", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in malignant peripheral nerve sheath tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant. 3) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 36067829, 24366910, 30099373)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250606, "diseases": [ { "symbols": { "mondo": "MONDO:0017827" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105134" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Malignant Peripheral Nerve Sheath Tumor" ], "normalized_cancer": [ "Malignant Peripheral Nerve Sheath Tumor" ], "symbols": { "medgen": "C0751690", "mondo": "MONDO:0017827" }, "names": [ "Malignant Peripheral Nerve Sheath Tumor" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253606" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND IDH-wildtype glioblastoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in IDH-wildtype glioblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28990704, 23552385, 29105198, 29532523, 24127995)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241119, "diseases": [ { "symbols": { "mondo": "MONDO:0850335" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105125" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Idh-Wildtype Glioblastoma" ], "symbols": { "medgen": "CN372125", "mondo": "MONDO:0850335" }, "names": [ "Idh-Wildtype Glioblastoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253607" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Diffuse leptomeningeal glioneuronal tumor", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse leptomeningeal glioneuronal tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 26994902, 32605662, 36382112)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20231207, "diseases": [ { "symbols": { "mondo": "MONDO:0858956" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105110" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Diffuse Leptomeningeal Glioneuronal Tumor" ], "normalized_cancer": [ "Diffuse leptomeningeal glioneuronal tumor" ], "symbols": { "medgen": "C4329735", "mondo": "MONDO:0858956" }, "names": [ "Diffuse Leptomeningeal Glioneuronal Tumor" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253608" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nodular ganglioneuroblastoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in nodular ganglioneuroblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 22142829, 26121087, 34331515)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20240320, "diseases": [ { "symbols": { "mondo": "MONDO:0003325" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105113" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Nodular Ganglioneuroblastoma" ], "symbols": { "medgen": "C1517445", "mondo": "MONDO:0003325" }, "names": [ "Nodular Ganglioneuroblastoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253609" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Polymorphous low grade neuroepithelial tumor of the young", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in polymorphous low grade neuroepithelial tumor of the young, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 27812792, 29701169, 30926558, 31520766, 31617914)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20240531, "diseases": [ { "symbols": { "mondo": "MONDO:0858959" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105118" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Polymorphous Low Grade Neuroepithelial Tumor The Young" ], "normalized_cancer": [ "Low-Grade Neuroepithelial Tumor" ], "symbols": { "medgen": "C5556330", "mondo": "MONDO:0858959" }, "names": [ "Polymorphous Low Grade Neuroepithelial Tumor The Young", "Polymorphous Low Grade Neuroepithelial Tumour The Young" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253610" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Diffuse low-grade glioma, MAPK pathway–altered", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse low-grade glioma, MAPK pathway–altered, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20240904, "diseases": [ { "symbols": { "mondo": "MONDO:0859614" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105121" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Diffuse Low-Grade Glioma, Mapk Pathway???Altered" ], "normalized_cancer": [ "Low-Grade Glioma, NOS" ], "symbols": { "medgen": "CN372173", "mondo": "MONDO:0859614" }, "names": [ "Diffuse Low-Grade Glioma, Mapk Pathway???Altered" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253611" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Benign metanephric tumor", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in benign metanephric tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 26796506, 26014474, 27769870, 32371339)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250130, "diseases": [ { "symbols": { "mondo": "MONDO:0018738" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105133" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Benign Metanephric Tumor" ], "normalized_cancer": [ "Benign metanephric tumor", "Benign metanephric tumour" ], "symbols": { "medgen": "C5681098", "mondo": "MONDO:0018738" }, "names": [ "Benign Metanephric Tumor", "Benign Metanephric Tumour" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253612" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Dysembryoplastic neuroepithelial tumor", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in dysembryoplastic neuroepithelial tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25346165, 26810070, 23442159, 31617914, 32164789)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20251105, "diseases": [ { "symbols": { "mondo": "MONDO:0005505" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105140" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Dysembryoplastic Neuroepithelial Tumor" ], "normalized_cancer": [ "Dysembryoplastic Neuroepithelial Tumor" ], "symbols": { "medgen": "C1266177", "mondo": "MONDO:0005505", "human_phenotype_ontology": "HP:0033703" }, "names": [ "Dysembryoplastic Neuroepithelial Tumor" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253613" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Pleomorphic xanthoastrocytoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in pleomorphic xanthoastrocytoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 15035987, 12068308, 19251651, 26343582). 4) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 21274720, 21479234, 30051528, 32619305, 32289278)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250512, "diseases": [ { "symbols": { "mondo": "MONDO:0016690" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105547" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Pleomorphic Xanthoastrocytoma" ], "normalized_cancer": [ "Pleomorphic Xanthoastrocytoma" ], "symbols": { "medgen": "C0334586", "mondo": "MONDO:0016690", "human_phenotype_ontology": "HP:0033682" }, "names": [ "Pleomorphic Xanthoastrocytoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253602" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Alveolar rhabdomyosarcoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in alveolar rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 22142829, 12068308, 24436047)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241003, "diseases": [ { "symbols": { "mondo": "MONDO:0009994" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105120" } ], "submission_description": [], "diseases": [ { "pub_med": [ 21829230 ], "normalized_disease": [ "Alveolar Rhabdomyosarcoma" ], "normalized_cancer": [ "Alveolar Rhabdomyosarcoma" ], "symbols": { "orphanet": "780", "omim": "268220", "medgen": "C0206655", "mondo": "MONDO:0009994", "human_phenotype_ontology": "HP:0006779" }, "names": [ "Alveolar Rhabdomyosarcoma", "Alveolar Rhabdomyosarcoma", "Alveolar Rhabdomyosarcoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253601" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neuroblastoma", "submissions": [ { "submitter_date": 20251120, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in neuroblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15035987, 12068308, 19251651, 26343582). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 22142829, 26121087, 34331515, 33056981)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241223, "diseases": [ { "symbols": { "mondo": "MONDO:0005072" } } ], "method": "clinical testing", "date_updated": 20251122, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV007105132" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Neuroblastoma" ], "symbols": { "medgen": "C0027819", "orphanet": "635", "mesh": "D009447", "mondo": "MONDO:0005072", "human_phenotype_ontology": "HP:0006738" }, "names": [ "Neuroblastoma" ] } ], "date_created": 20251122, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV006253600" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cardio-facio-cutaneous syndrome", "submissions": [ { "submitter_name": "GeneReviews", "submitter_date": 20160303, "submission_description": [], "review_description": "not provided", "diseases": [ { "symbols": { "medgen": "C1275081" } } ], "method": "literature only", "date_updated": 20221001, "origin": "somatic", "clinical_significance": [ "not provided" ], "review_status": "no classification provided", "accession_id": "SCV000264636" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Cardiofaciocutaneous Syndrome" ], "symbols": { "orphanet": "1340", "omim": "115150", "medgen": "C1275081", "mondo": "MONDO:0015280" }, "names": [ "Cardiofaciocutaneous Syndrome", "Cardiofaciocutaneous Syndrome", "Cardiofaciocutaneous Syndrome" ], "disease_mechanism": "gain of function" } ], "date_created": 20160305, "clinical_significance": [ "not provided" ], "review_description": "not provided", "allele_id": 29000, "accession_id": "RCV000208763" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Epithelioid Glioblastoma", "submissions": [ { "submitter_date": 20250903, "submission_description": [ "Variant has Tier I clinical significance as a diagnostic inclusion criterion in Epithelioid Glioblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28990704, 23552385, 29105198, 29532523, 24127995)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20241119, "diseases": [ { "names": [ "Epithelioid Glioblastoma" ] } ], "method": "clinical testing", "date_updated": 20250906, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV006312223" } ], "submission_description": [], "diseases": [ { "symbols": { "medgen": "C4289580" }, "names": [ "Epithelioid Glioblastoma" ] } ], "date_created": 20250906, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV005630705" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Spindle cell sarcoma", "submissions": [ { "submitter_date": 20251201, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in spindle cell sarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant. 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 12068308, 22142829, 32476297)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20250116, "diseases": [ { "symbols": { "mondo": "MONDO:0002927" } } ], "method": "clinical testing", "date_updated": 20251207, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV006312224" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Spindle Cell Sarcoma" ], "normalized_cancer": [ "Spindle cell sarcoma" ], "symbols": { "medgen": "C0205945", "mondo": "MONDO:0002927" }, "names": [ "Spindle Cell Sarcoma" ] } ], "date_created": 20250906, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV005630704" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Embryonal rhabdomyosarcoma", "submissions": [ { "submitter_date": 20251201, "submission_description": [ "Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMID: 17496922). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 22142829, 12068308, 24436047)." ], "submitter_name": "Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital", "review_date": 20240808, "diseases": [ { "symbols": { "mondo": "MONDO:0009993" } } ], "method": "clinical testing", "date_updated": 20251207, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV006312222" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Embryonal Rhabdomyosarcoma" ], "normalized_cancer": [ "Embryonal Rhabdomyosarcoma" ], "symbols": { "medgen": "C0206656", "mondo": "MONDO:0009993", "human_phenotype_ontology": "HP:0006743" }, "names": [ "Embryonal Rhabdomyosarcoma", "Botryoid Rhabdomyosarcoma ( Erms)", "Spindle Cell Rhabdomyosarcomas ( Erms)" ] } ], "date_created": 20250906, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV005630703" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Thyroid gland undifferentiated (anaplastic) carcinoma", "submissions": [ { "submitter_date": 20240829, "submission_description": [ "This mutation has been reported in anaplastic thyroid cancers (PMID: 29615459; PMID: 29742974; PMID: 33029242). The anaplastic thyroid cancer patients with this mutation had a median progression free survival of 6.7 months (PMID: 37059834)." ], "submitter_name": "National Institute of Cancer Research, National Health Research Institutes", "review_date": 20240201, "diseases": [ { "symbols": { "mesh": "D065646" } } ], "method": "clinical testing", "date_updated": 20240929, "origin": "somatic", "clinical_significance": [], "review_status": "no assertion criteria provided", "accession_id": "SCV005326492" } ], "submission_description": [], "diseases": [ { "normalized_cancer": [ "Thyroid", "Anaplastic Thyroid Cancer" ], "symbols": { "medgen": "C0238461", "mesh": "D065646", "mondo": "MONDO:0006468", "human_phenotype_ontology": "HP:0011779" }, "names": [ "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma", "Thyroid Carcinoma, Anaplastic, Somatic" ], "normalized_disease": [ "Thyroid Gland Undifferentiated (Anaplastic) Carcinoma" ], "keyword": "Neoplasm" } ], "date_created": 20240929, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV004719648" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Malignant neoplastic disease", "submissions": [ { "submitter_name": "Investigational Cancer Therapeutics, MD Anderson Cancer Center", "submitter_date": 20200824, "submission_description": [], "review_description": "Likely pathogenic", "diseases": [ { "normalized_disease": [ "Cancer" ], "normalized_cancer": [ "Cancer" ], "names": [ "Cancer" ] } ], "method": "research", "date_updated": 20200829, "origin": "unknown", "clinical_significance": [ "Likely pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001424772" } ], "submission_description": [], "diseases": [ { "pub_med": [ 26389258, 26389204 ], "normalized_disease": [ "Cancer" ], "normalized_cancer": [ "Cancer" ], "symbols": { "medgen": "C0006826", "mondo": "MONDO:0004992" }, "names": [ "Cancer", "Cancer" ] } ], "date_created": 20200829, "clinical_significance": [ "Likely pathogenic" ], "review_description": "Likely pathogenic", "allele_id": 29000, "accession_id": "RCV001254874" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Colorectal cancer", "submissions": [ { "submitter_date": 20240216, "submission_description": [ "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers." ], "submitter_name": "CIViC knowledgebase, Washington University School of Medicine", "review_date": 20190228, "diseases": [ { "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "Colorectal cancer" ], "names": [ "Colorectal Cancer" ] } ], "method": "curation", "date_updated": 20240220, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV004565362" } ], "submission_description": [], "diseases": [ { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] } ], "date_created": 20200329, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV001030023" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cerebral arteriovenous malformation", "submissions": [ { "submitter_name": "Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School", "submitter_date": 20190905, "submission_description": [], "review_description": "Pathogenic", "diseases": [ { "symbols": { "omim": "108010" } } ], "method": "research", "date_updated": 20250413, "origin": "somatic", "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000992587" } ], "submission_description": [], "diseases": [ { "normalized_disease": [ "Arteriovenous Malformations of the Brain" ], "symbols": { "orphanet": "46724", "omim": "108010", "medgen": "C0917804", "mondo": "MONDO:0007154", "human_phenotype_ontology": "HP:0002408" }, "names": [ "Arteriovenous Malformations of the Brain", "Cerebral Arteriovenous Malformations", "Arteriovenous Malformations of the Brain" ] } ], "date_created": 20191217, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 29000, "accession_id": "RCV000860020" }, { "variation_id": 13961, "variant_id": 10190071404531360004, "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm", "submissions": [ { "submitter_date": 20250304, "submission_description": [], "submitter_name": "Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital", "review_date": 20250304, "diseases": [ { "symbols": { "medgen": "C0027651" } } ], "method": "clinical testing", "date_updated": 20250311, "origin": "somatic", "clinical_significance": [], "review_status": "criteria provided, single submitter", "accession_id": "SCV005094141" } ], "submission_description": [], "diseases": [ { "pub_med": [ 22918138, 23619274, 34131312 ], "normalized_cancer": [ "Neoplasm", "Neoplasms", "Neoplasm (disease)", "tumor" ], "symbols": { "medgen": "C0027651", "mesh": "D009369", "mondo": "MONDO:0005070", "human_phenotype_ontology": "HP:0006741" }, "names": [ "Neoplasm", "Neoplasms", "Neoplasm", "Neoplasm" ], "normalized_disease": [ "Neoplasm" ], "keyword": "neoplasm" } ], "date_created": 20170308, "clinical_significance": [], "allele_id": 29000, "accession_id": "RCV000443448" } ], "main_data": "conflicting interpretations of pathogenicity **1**", "names": [ "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)", "VAL640GLU" ], "variant_type": "SNV" } ], "publications": { "publications": [ { "pub_med_id": 40291070 }, { "pub_med_id": 39333321 }, { "pub_med_id": 38269481 }, { "pub_med_id": 37629086 }, { "pub_med_id": 37296851 }, { "pub_med_id": 37240418 }, { "pub_med_id": 37231247 }, { "referenced_by": [ "CIViC" ], "pub_med_id": 37059834 }, { "pub_med_id": 36801912 }, { "pub_med_id": 36579983 }, { "pub_med_id": 36475784 }, { "referenced_by": 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"molecular_profile": { "evidence_item_ids": [ 11696 ], "name": "BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation", "summary": null, "variant": [ { "gene": "BRAF", "hgvs": "V600E", "variant_ids": [ "10190071404531360004" ] } ] }, "molecular_profile_civic_id": 4748 }, { "molecular_profile": { "evidence_item_ids": [ 90 ], "name": "BRAF V600E AND NF1 Loss", "summary": null, "variant": [ { "gene": "BRAF", "hgvs": "V600E", "variant_ids": [ "10190071404531360004" ] } ] }, "molecular_profile_civic_id": 5379 }, { "molecular_profile": { "evidence_item_ids": [ 1906 ], "name": "BRAF V600E AND GNAS R201C", "summary": null, "variant": [ { "gene": "BRAF", "hgvs": "V600E", "variant_ids": [ "10190071404531360004" ] }, { "gene": "GNAS", "hgvs": "R201C", "variant_ids": [ "10190200574844200004" ] } ] }, "molecular_profile_civic_id": 5491 }, { "molecular_profile": { "evidence_item_ids": [ 1905 ], "name": "BRAF V600E AND ARAF S490T", "summary": null, "variant": [ { 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"KRAS", "hgvs": "G12D", "variant_ids": [ "10190120253982840004" ] } ] }, "molecular_profile_civic_id": 5806 } ] }, { "asco_entry": null, "clinical_significance": "Positive", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/80", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Thyroid nodule with BRAF V600E mutation is highly correlated with papillary thyroid cancer.", "evidence_status": "accepted", "evidence_type": "Diagnostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24570209 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", 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"assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Nutlin-3", "PLX4720" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/97", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Combined nutlin-3 and PLX4720 administration to athymic nude mice subcutanousely injected with the A357 melanoma cell line with a BRAF V600E mutation effectively inhibited tumor growth significantly more than single agent therapy.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2025-06-11 17:06:50 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23812671 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Capecitabine", "Bevacizumab", "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/98", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Capecitabine, bevacizumab and vemurafenib combination therapy resulted in 100% tumor growth inhibition (TGI) and 190% increased lifespan (ILS) compared to vehicle treated controls. Seven mice experienced partial response and two experienced complete response. Triplet therapy resulted in better TGI and ILS compared to any agent in isolation or capecitabine + vemurafenib doublet therapy (p <0.05, p <0.0001, for all comparisons).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Bevacizumab", "Capecitabine", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22180495 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/99", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "This preclinical study examined vemurafenib efficacy on various colorectal cancer cell lines and in mouse xenograft experiments. Of the cell lines tested, six harbored BRAF V600E (and WT KRAS) and three harbored BRAF WT (but mutant KRAS). Of the six BRAF V600E expressing cell lines, four were sensitive to vemurafenib (IC50 ranging between 0.025 and 0.35 uM; HT29, Colo205, Colo741, LS411N). Cell lines expressing the BRAF V600E mutation responded better to vemurafenib treatment than cells wildtype for BRAF as measured by reduced cellular proliferation and inhibition of MET and ERK phosphorylation (none of the three BRAF wt cell lines had IC50s less than 10uM). Authors note that one of the vemurafenib-resistant cell lines harboring BRAF V600E (RKO) harbored a concurrent activating PIK3CA H1047R mutation. Nude, athymic mice with HT29 xenografts treated with vemurafenib experienced substantial tumor inhibition and increased lifespan at every dose tested, though authors found 75 mg/kg twice daily to be optimal (95% tumor growth inhibition, 90% increased lifespan compared to vehicle treated controls).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22180495 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/102", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Unlike other studies that suggest a poorer outcome, BRAF mutation in this study was not correlated with poorer prognosis in papillary thyroid cancer.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24354346 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/103", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24594804 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/104", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "BRAF V600E is correlated with shorter disease-free and overall Survival in a Spanish cohort of melanoma patients.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24388723 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/105", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "BRAF mutation correlated with poor prognosis in papillary thyroid cancer in both older (>65 yo) and younger (<65 yo) cohorts.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21594703 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/106", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "BRAF V600E is correlated with poor prognosis in papillary thyroid cancer in a study of 187 patients with PTC and other thyroid diseases.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24396464 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/107", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "V600E is correlated with disease recurrence in both age cohorts (>65 and <65 yo).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21594703 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/126", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "This was a retrospective study of 691 cetuximab treated patients with metastatic, chemotherapy refractory colorectal cancer. Of those, 30 patients harbored BRAF V600E, were KRAS, NRAS and PIK3CA wt, and had individual response data. One patient (who harbored BRAF V600E in low copy number) responded, 11 had stable disease, and 18 progressed. Treatments included cetuximab + irinotecan (n=20), cetuximab monotherapy (n=5), cetuximab + FOLFIRI (n=4), and cetuximab + oxaliplatin + 5FU (n=1). Median PFS was 8 weeks (2-32 weeks), median OS was 25 weeks (4-237 weeks), and median number of previous chemotherapy lines was 2 (0-4). Median age was 61 years old (42-78) and there were 16 males and 14 females. Authors concluded that BRAF mutation (23/24 of mutants were BRAF V600E) was strongly associated with poor response to cetuximab and suggested that mutation status of BRAF is more informative than those of NRAS and PIK3CA exon 20 for predicting cetuximab response (second only to KRAS).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab" ], "phenotypes": null, "pub_med_references": [ 20619739 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/463", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In patients with multiple myeloma, those with BRAF V600E had shorter overall survival than wild-type.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23612012 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/656", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In patients with papillary thyroid cancer harboring both BRAF V600E and the TERT promotor mutation C228T (N=35), recurrence-free survival is worse than in patients harboring one of these mutations (N=159 BRAF, N=26 TERT promoter mutated) or no mutations in either gene (N=287)(P<0.001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 25024077 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Pictilisib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/757", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "One patient with BRAF V600E mutated melanoma (with no detected PI3K pathway deregulation) had a partial response on treatment with pictilisib, a PI3K inhibitor, for 9.5 months. Study was a phase-1 with 60 patients enrolled.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Pictilisib" ], "phenotypes": null, "pub_med_references": [ 25370471 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Substitutes", "drugs": [ "Cetuximab", "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/816", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "This meta-analysis of 7 randomized control trials evaluating overall survival (OS) (8 for progression free survival) could not definitely state that survival benefit of anti-EGFR monoclonal antibodies is limited to patients with wild type BRAF. In other words, the authors believe that there is insufficient data to justify the exclusion of anti-EGFR monoclonal antibody therapy for patients with mutant BRAF. In these studies, mutant BRAF specifically meant the V600E mutation.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab, Panitumumab" ], "phenotypes": null, "pub_med_references": [ 25989278 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "MEK Inhibitor RO4987655" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/994", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "This was a phase I expansion and pharmacodynamic study of oral MEK inhibitor RO4987655 on advanced cancer. Of 17 patients with BRAF V600E melanoma, 4 achieved partial response, 5 experienced stable disease lasting longer than 16 weeks, and 8 experienced disease progression (including 2 with prior vemurafenib treatment). One of the partial responders had a concomitant EGFR mutation, and two of the stable disease patients had other concomitant mutations (in RET or MET). The median days on treatment was 113 (18-366) for BRAF V600E melanoma patients and 107 (17-323) for BRAF V600 wildtype patients (n=23). Patients with BRAF V600E mutant melanoma experienced similar response rates (24% vs 20%) and rates of metabolic response measured by decrease in FDG uptake assessed by FDG-PET (86% vs 75%) compared to non-BRAF mutant patients. Patients with melanoma, either BRAF wt or V600E, experienced significant decreases in Ki67 expression by day 15 of MEK inhibitor treatment (P<0.02). The authors conclude that RO4987655 has clinical activity in BRAF V600E and BRAF wt melanoma.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 24947927 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Dactolisib", "Selumetinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1005", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "49 BRAF-mutant melanoma cell lines from patients not previously treated with BRAF inhibition were analyzed. 21 exhibited primary resistance to BRAF inhibition using PLX4720. Inhibition of MEK1/2 (AZD6244 [selumetinib]) and PI3K/mTOR (BEZ235 [dactolisib]) was the most effective approach to counteract resistance in comparison to inhibition with the PLX4720 (progenitor of vemurafenib)-BEZ235 (where response was assessed by apoptosis, viability, p-ERK, p-Akt inhibition).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Dactolisib", "Selumetinib" ], "phenotypes": null, "pub_med_references": [ 26678033 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Positive", "disease": "Hairy Cell Leukemia", "doid": "285", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1127", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In 47 patients with Hairy Cell Leukemia, sequencing discovered a V600E mutation in all 47 of the sequenced patients.", "evidence_status": "accepted", "evidence_type": "Diagnostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21663470 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cancer", "doid": "162", "drug_interaction_type": null, "drugs": [ "Cobimetinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1141", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Preclinical study analyzing the differential response to MEK inhibitors in KRAS and BRAF mutant cancer cell lines and mouse xenografts. Inhibition of active, phosphorylated MEK by GDC-0973 (cobimetinib) is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours. This study provides mechanistic rationale for improved efficacy of cobimetinib in BRAF-mutant models compared to MEK inhibitors acting through an alternative mechanism (GDC-0623 and G-573).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Cobimetinib" ], "phenotypes": null, "pub_med_references": [ 23934108 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1398", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The BRIM-3 Phase III trial NCT01006980 assessed BRAF inhibitor vemurafenib versus dacarbazine in 598 patients with treatment naive metastatic melanoma and confirmed V600E mutation. Significant differences were seen in overall survival (13.3 months with vemurafenib vs. 10.0 months with dacarbazine) and median progression free survival (6.9 months with vemurafenib vs. 1.6 months with dacarbazine)", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT01006980" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 24508103 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1405", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "In this Phase II pilot study (NCT00405587) of BRAF V600 inhibitor vemurafenib in 21 metastatic colorectal cancer (CRC) patients with BRAF V600E, one patient had a durable 21 week partial response, and seven patients had 8 week stable disease as best response. Median progression free survival was 2.1 months and median overall survival was 7.7 months. The authors conclude that single agent vemurafenib did not show meaningful activity in V600E CRC, in contrast to the significant vemurafenib activity against V600 in melanoma.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT00405587" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26460303 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Reduced Sensitivity", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1406", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In trial NCT00880321, dabrafenib was tested in various solid tumor types harboring mutant BRAF after establishing dosage of 150 mg twice daily. In nine colorectal cancer patients with established V600E mutation, 1 confirmed response, 7 instances of stable disease, and 1 case of progressive disease was seen, which contrasted strongly with a 56% confirmed response rate seen in metastatic V600E melanoma patients similarly treated in the same study.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2025-12-17 19:06:25 UTC", "nct_ids": [ "NCT00880321" ], "normalized_drug": [ "Dabrafenib" ], "phenotypes": null, "pub_med_references": [ 22608338 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Cetuximab", "Gefitinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1408", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "5 of 7 colorectal cancer (CRC) cell lines with BRAF V600E mutation were resistant to treatment with the BRAF inhibitor vemurafenib. An RNAi screen in the WiDr cell line (a V600E CRC line) identified EGFR as an enhancer for survival when exposed to vemurafenib. Treatment with vemurafenib and EGFR inhibitor (cetuximab or gefitinib) in V600E CRC cells (WiDr, VACO432 and KM20) showed inhibited growth as well as induction of the cleaved PARP apoptotic marker. WiDr and VACO432 cells were injected into immunodeficient mice. Modest response was seen with vemurafenib treatment, while combination treatment showed considerable tumor growth inhibition as compared to control.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab", "Gefitinib", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22281684 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Skin Melanoma", "doid": "8923", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1409", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "Phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. A relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression was observed with vemurafenib as compared with dacarbazine (P<0.001 for both comparisons).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT01006980" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 21639808 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Skin Melanoma", "doid": "8923", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1410", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Phase 2 trial in 132 patients with previously treated metastatic melanoma with BRAF V600E mutation. Confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Median overall survival was 15.9 months (95% CI, 11.6 to 18.3).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT00949702" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22356324 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Panitumumab", "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1413", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "Treatment response to mutant BRAF inhibitor vemurafenib and EGFR inhibitor panitumumab was assayed in 12 patients with metastatic colorectal cancer (CRC) who had progressed on chemotherapy. Two patients had confirmed partial responses, and 2 showed stable disease over 6 months. The authors conclude that although some efficacy is seen, only a small subset of patients respond to this treatment and the responses are not durable.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Panitumumab", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 25589621 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1414", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A 73 year old patient with prior history of breast cancer presented with metastatic papillary thyroid carcinoma. After two treatments of I-131 a comprehensive tumor profile revealed BRAF V600E as the only genetic alteration on a near diploid genome with trisomy 1q. Vemurafenib treatment resulted in improvement of symptoms and considerable reductions in tumor mass, and after 23 months the patient remained on therapy with well controlled disease.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 24987354 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Cobimetinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1421", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 344 had V600E mutation. 174 patients were treated with vemurafenib and placebo, and 170 were treated with vemurafenib and cobimetinib and tested for progression free survival. 88 of 174 monotherapy group patients had an event with median progression free survival of 6.5 months. In the combination group 58 of 174 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.57 (0.41-0.80).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01689519" ], "normalized_drug": [ "Cobimetinib, Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 25265494 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "GDC-0879", "Dactolisib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1428", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In a mouse model of BRAF V600E colorectal cancer, western blots from tumors in mice treated with BRAF inhibitor GDC-0879 and PI3K/mTOR inhibitor BEZ235 showed stronger reduction in phospho-Akt and phospho-S6 than PI3K/mTOR inhibitor alone, and combination inhibition also resulted in stronger phospho-ERK inhibition in tumors than did BRAF inhibition alone. Increased apoptosis in tumors was seen in dual treatment conditions with increased TUNEL-positive cells. In vehicle treated mice, area of colon covered by tumor increased, while treatment with single agent inhibitors caused growth inhibition resulting in no change in colon area covered by tumors. Administration of dual inhibitors induced tumor regression apparent in a decrease of colonic area covered by tumors over the course of treatment.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Dactolisib" ], "phenotypes": null, "pub_med_references": [ 23549875 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Gastrointestinal Neuroendocrine Tumor", "doid": "0050626", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Vemurafenib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1430", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "BRAF mutations were identified in 9% of 108 cases of high-grade colorectal neuroendocrine tumors (80% V600E). Two patients were treated with a combination of BRAF and MEK inhibition and exhibited durable response (beyond 7 and 9 months, respectively). Urinary BRAF V600E tumor DNA correlated with disease response in one of the patients. BRAF and MEK inhibition was either dabrafenib+trametinib (case 1) or vemurafenib+trametinib (case 2).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib", "Trametinib", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 27048246 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1552", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 908 patients with colorectal cancer, 45 patients had BRAF V600E mutations and 589 patients were BRAF wild type. BRAF V600E mutations were more likely to be proximal tumors (68.9%, 20.7%; p<0.0001), they were more likely to be poorly differentiated (17.7%, 1.9%; p<0.0001), they were more likely to be mucinous carcinoma type (20.0%, 4.2%; p=0.0003), they were more likely to have lymphatic invasion (77.6%, 49.9%; p=0.0003), and they had a shorter survival time (31.1 mo, 41.6 mo; p=0.001). The 3-year survival rate was significantly poorer in the V600E group when compared to the wild type group (63.8%, 87.9%; p<0.0001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 27404270 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Hairy Cell Leukemia", "doid": "285", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1579", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Two clinical trials evaluated the effects of vemurafenib in 54 patients with BRAF (V600E) positive hairy-cell leukemia. The overall response rate was 98% with 19/54 having a complete response and 34/54 having a partial response. In the Italian study (n=25), the median relapse-free survival was 9 months and in the U.S. study (n=24), rate of progression-free survival was 73% with overall survival rate of 91%.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT01711632" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26352686 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1589", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "Case report of a patient with BRAF V600E mutant metastatic colorectal cancer. Combined EGFR and BRAF inhibition (panitumumab and vemurafenib) showed an initial partial response for 4 months with subsequent disease progression.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Panitumumab", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 27325282 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1591", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Open-label non-randomised phase 2 trial in patients with recurrent or metastatic BRAF V600E mutant papillary thyroid cancer refractory to radioactive iodine. Patients had (cohort 2) or had not (cohort 1) previously been treated with VEGFR inhibitors. 51 patients were enrolled (26 cohort 1, 25 cohort 2). In cohort 1, partial response was achieved in ten (38.5%) patients. Nine patients achieved stable disease for at least 6 months (35%). Median PFS was 18.2 months and median OS not reached after a median follow-up pf 18.8 months. In cohort 2, six patients (27.3%) achieved a partial response and another six patients achieved stable disease for at least six months. Median PFS was 8.9 months and median OS was 14.4. months.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT01286753" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 27460442 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1698", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A 65-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and he received an autologous stem cell transplant. Sequencing of the recurrent tumor harbored BRAF V600E mutation and he was treated with vemurafenib. After 7 weeks of treatment, the patient relapsed and died.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 24997557 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Multiple Myeloma", "doid": "9538", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1699", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A 54-year-old man presented with stage II myeloma. He was initially treated with chemotherapy and received an autologous stem cell transplant. Genomic profiling of the bone biopsy revealed BRAF V600E activating mutation and the patient was treated with vemurafenib. At 4-months post treatment (time of case study report) the patient maintains near-resolution of hypermetabolic lesions.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 24997557 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1749", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Multicenter, phase 1, dose-escalation trial of PLX4032 (Vemurafenib). Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients (N=37/48). Patients without the V600E mutation had evidence of tumor regression.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 20818844 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Irinotecan", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1902", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Phase 1b study of vemurafenib, cetuximab and irinotecan in 19 patients with colorectal cancer (1 with appendiceal cancer). Six of 17 evaluable patients achieved an objective response, 15 patients total had either stable disease or radiographic response (the patient with appendiceal cancer had disease progression). Estimated median PFS was 7.7 months. Effect of the combined treatment was also observed in xenograft and cell line studies.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT01787500" ], "normalized_drug": [ "Cetuximab", "Irinotecan", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 27729313 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1940", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 468 colorectal cancer samples, 61 patients had micro-satellite instability and there was a statistically significantly better prognosis for BRAF WT patients relative to BRAF (V600E)-mutated patients (Log-rank P=0.0903).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": null, "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Substitutes", "drugs": [ "Panitumumab", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2115", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In metastatic colorectal cancer patients with wildtype KRAS status, those with a BRAF V600E mutation were less likely to respond to treatment with cetuximab or panitumumab than those with wildtype BRAF (0% vs. 32% , P=0.029). Regardless of KRAS status, patients with BRAF mutations had reduced progression-free and overall survival (P=0.0107 and P <0.0001, respectively). Transfection of the colorectal cancer cell line DiFi with a BRAF V600E expression vector conferred decreased sensitivity to cetuximab and panitumumab in comparison to cells transfected with empty vector.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab, Panitumumab" ], "phenotypes": null, "pub_med_references": [ 19001320 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2116", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of metastatic colorectal cancer patients who received 5-FU-based first-line chemotherapy, those with BRAF V600E mutations had reduced progression-free survival (4.3mo vs. 12.5mo, HR:4.9, 95%CI:2.7-9.0, P<0.0001, univariate analysis; HR:4.0, 95%CI:2.2-7.4, P<0.0001, multivariate analysis) and reduced overall survival (10.9mo vs. 40.5mo, HR:4.5, 95%CI:2.4-8.4, P<0.0001, univariate analysis; HR:4.1, 95%CI:2.1-8.0, P<0.0001, multivariate analysis) compared to those with wildtype BRAF.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-12-03 08:11:19 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 19603024 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Oxaliplatin" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2117", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Of 100 metastatic colorectal cancer patients treated with oxaliplatin-based first-line therapy, the 6 patients with either BRAF V600E or D594K had reduced progression-free survival compared to 94 patients with wildtype BRAF (5.0mo vs. 11.7mo, HR:6.4, 95%CI:2.6-15.6, P<0.0001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Oxaliplatin" ], "phenotypes": null, "pub_med_references": [ 19603024 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Irinotecan" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2118", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The presence of BRAF V600E or D594K was associated with reduced progression-free survival in 5 patients with metastatic colorectal cancer treated with irinotecan-based first line therapy (3.5mo vs. 12.8mo, HR:4.1, 95%CI:1.5-11.3, P=0.006) when compared to 39 patients with wildtype BRAF.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Irinotecan" ], "phenotypes": null, "pub_med_references": [ 19603024 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Oxaliplatin", "Bevacizumab", "Capecitabine" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2121", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of metastatic colorectal cancer patients treated with capecitabine, oxaliplatin, and bevacizumab, those with BRAF V600E mutations had reduced progression-free survival (5.9mo vs. 12.2mo, P=0.003) and reduced overall survival (15.0mo vs. 24.6mo, P=0.002) compared to those with wildtype BRAF.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Bevacizumab, Capecitabine, Oxaliplatin" ], "phenotypes": null, "pub_med_references": [ 19571295 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2135", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 322 advanced melanoma patients with BRAF-V600E (N=281), BRAF-V600K (N=40), or both mutations (N=1), treatment with trametinib was associated with improved progression-free survival (4.8mo vs. 1.5mo; HR: 0.45, 95% CI: 0.33-0.63, P<0.001) compared to chemotherapy control group. Additionally, treatment with trametinib was associated with increased 6-month overall survival (HR: 0.54, 95% CI: 0.32-0.92, P=0.01). The authors note similar outcomes for the primary efficacy population (V600E only) and the intention-to-treat population.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01245062" ], "normalized_drug": [ "Trametinib" ], "phenotypes": null, "pub_med_references": [ 22663011 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2137", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a study of 102 papillary thyroid cancer patients with a 15 year median follow-up time, those with BRAF V600E mutations had reduced overall survival compared to those with wildtype BRAF (P=0.015, log-rank test). The presence of BRAF V600E was associated with poorer outcome as defined by persistent disease or death (Odds ratio:14.63, 95%CI:1.28-167.29, P=0.03, multivariate analysis.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 18682506 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2362", "evidence_direction": "Does Not Support", "evidence_level": "C", "evidence_statement": "This study examined outcomes of 240 rectum cancer patients treated with total mesorectal excision therapy. Tumor samples were obtained at the time of surgery and genotyped for BRAF exon 15 mutations. BRAF V600E was identified in 5 cases. The authors reported that no differences were found in overall survival between patients with and without BRAF mutations (P > 0.1).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 19903786 ], "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/2503", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a meta-analysis of 8 studies, papillary thyroid cancer patients with BRAF V600E mutation had a higher frequency of recurrence and persistent disease compared to those with wildtype BRAF (28.5% vs. 12.8% , Risk ratio:2.14, 95%CI:1.67-2.74, P<0.00001).", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21882184 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3017", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "Patients with BRAF V600E-mutant NSCLC (n=57) were enrolled into a phase 2, multicentre, non-randomised, open-label study, administering dabrafenib plus trametinib. The overall response rate was 36/57 (63.2%, [95% CI 49.3-75.6]) and the median progression-free survival was 9.7 months (95% CI 6.9-19.6). At data cutoff (11.6 months of follow-up), 18/36 (50%) confirmed responses were ongoing and 23/57 (40%) of patients had died.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01336634" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 27283860 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "FOLFOX-4 Regimen", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3739", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a retrospective study of 148 treatment naive metastatic colorectal cancer patients, patients with BRAF V600E and wildtype NRAS/KRAS (n=14) mutation treated with FOLFOX4 plus cetuximab were associated with a decreased progression free survival (7.2mo vs. 9.7mo, HR:0.39, 95% CI:0.21-0.72, P=0.0017), and decreased overall survival (11.7mo vs. 28.5mo, HR:0.23, 95% CI:0.12-0.41, P<0.0001), as compared to patients with wildtype BRAF, NRAS and KRAS.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:24 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab", "Folfox" ], "phenotypes": null, "pub_med_references": [ 25666295 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3750", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a phase 2 clinical trial (NCT00949702) of 132 BRAF mutation positive metastatic melanoma patients treated with vemurafenib monotherapy, patients harboring BRAF V600E (n=123) or V600K (n=9) mutations were associated with a favorable objective response rate (53% per RECIST v1.1 criteria, 70/132), with 6% (8/132) and 47% (62/132) of patients achieving complete response and partial response, respectively.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 23569304 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3755", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a clinical study (NCT01307397) of Polish, stage IIIC/IV, melanoma patients with metastases (n=75) harboring BRAF V600 mutation (as detected by cobas 4800 BRAF V600 Mutation Test), median overall survival was 61.9% (95% CI: 50.1-73.6) and median progression free survival was 7.4 months (95% CI: 5.5-9.2). Median duration of response was 7.4 months (95% CI: 5.7-9.2), with 3% (2/75) and 43% (29/75) of patients achieving a complete and partial response, respectively.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26557775 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3757", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a retrospective study of 300 stage IV melanoma patients, patients with BRAF V600E mutation (n=175) were associated with a 4.8% (8/167) complete response, a 58.1% (97/167) partial response and stable disease in 22.2% (37/167) of cases, while 15% (25/167) of patients harboring BRAF V600E experienced progressive disease.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 25524477 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Skin Melanoma", "doid": "8923", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3758", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600E mutation and treated with vemurafenib (n=317) were associated with a 51% response rate, as compared to a 64% response rate (p<0.001) in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=312). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01597908" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 25399551 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Childhood Pilocytic Astrocytoma", "doid": "6812", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3777", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "In a case report, a 28 month old patient with a cervicomedullary low grade glioma compatible with pilocytic astrocytoma which was resected had a second lesion consistent with a ganglioglioma 3 years later. This mass progressed under treatment at which point PCR amplification of BRAF exon 15 and subsequent Sanger sequencing the initial biopsy revealed the tumor harbored a BRAF V600E mutation. Based on these results, vemurafenib monotherapy was started and radiological and clinical response was noted after 3 months of treatment, which was sustained after 6 months of therapy. Prior to vemurafenib treatment, the patient had undergone tracheotomy, was treated with standard chemotherapy and underwent another surgery, but had developed progressive disease.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 25524464 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Ovarian Serous Carcinoma", "doid": "0050933", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3787", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A stage 4B, low-grade papillary serous ovarian adenocarcinoma patient, harboring a BRAF V600E mutation was associated with response to vemurafenib monotherapy. The patient was treated with standard chemotherapy, hormone therapy and bevacizumab prior to the identification of the BRAF V600E mutation; next, the patient was treated with paclitaxel and an anti-HER3 antibody and finally with vemurafenib, obtaining a partial response of greater than 1 year.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26490654 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Resistance", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/3827", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "One patient participating in a large retrospective study of EGFR monoclonal antibodies in metastatic colorectal cancer had a tumor which harbored BRAF V600E, was wildtype for NRAS, KRAS and PIK3CA, and had individual response data. This patient was was a male treated with panitumumab monotherapy as 1st line therapy who experienced progressive disease (PFS: 7 weeks; OS: 10 weeks).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Panitumumab" ], "phenotypes": null, "pub_med_references": [ 20619739 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cholangiocarcinoma", "doid": "4947", "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5902", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "Chemotherapy-refractory, metastatic cholangiocarcinoma with CNS involvement and a BRAF V600E mutation had a partial response at 8 weeks to dabrafenib and trametinib combination with complete radiologic regression at 12 weeks. At 6 months the patient was still on treatment.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 28480077 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Intrahepatic Cholangiocarcinoma", "doid": "4928", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5903", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "Two cases of patients with BRAF V600E positive, refractory intrahepatic cholangiocarcinoma showed excellent clinical and radiographic response to combination dabrafenib and trametinib treatment. One patient achieved complete remission at 6 months with progression at 9 months and the other partial remission at 2 months and no progression as of 5 months.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 28078132 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Intrahepatic Cholangiocarcinoma", "doid": "4928", "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5904", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "Dabrafenib and trametinib combination showed durable response for a patient with standard chemotherapy and radiation refractory, poorly differentiated, intrahepatic cholangiocarcinoma harboring BRAF V600E. At time of publication, 8.5 months, the patient was still on treatment.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 25435907 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cholangiocarcinoma", "doid": "4947", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Irinotecan", "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5906", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "A 31 year old patient with metastatic cholangiocarcinoma with BRAF V600E was treated with vemurafenib, panitumumab and irinotecan triplet therapy. By 2 months, 50% reduction of tumor volume was noted, including multiple lung metastases, complete clinical response was noted by CT 6 months post therapy and this treatment was continued.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Irinotecan", "Panitumumab", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26687137 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Lung Non-small Cell Carcinoma", "doid": "3908", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5958", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Within the BRAF mutant group, fourteen patients had refractory BRAF V600E-mutated NSCLC (adenocarcinoma, n = 13; sarcomatoid, n = 1). Six patients (43%; 95% CI, 18% to 71%) had objective responses (one CR, five PR), and two additional patients had SD > 120 days. The median DOR was 5 months (range, 4 to 14 months).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02091141" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Ovarian Cancer", "doid": "2394", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5959", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 4 patients with BRAF V600E mutant ovarian cancer, 2 had a partial response and one had stable disease > 120days.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02091141" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5960", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. Among 2 patients with BRAF V600E mutant colorectal cancer, 1 had a partial response.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02091141" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "2", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Anaplastic Thyroid Carcinoma", "doid": "0080522", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Pertuzumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5961", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant anaplastic thyroid cancer had a complete response.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02091141" ], "normalized_drug": [ "Pertuzumab", "Vemurafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Laryngeal Squamous Cell Carcinoma", "doid": "2876", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/5962", "evidence_direction": "Supports", "evidence_level": "C", "evidence_statement": "The phase 2a MyPathway study assigned patients with HER2, EGFR, BRAF or SHH alterations to treatment with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. One patient with BRAF V600E mutant laryngeal cancer had a partial response with vemurafenib.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02091141" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Anaplastic Thyroid Carcinoma", "doid": "0080522", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6045", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a phase 2 “basket” study of vemurafenib in BRAF V600-positive non-melanoma cancers, seven patients with anaplastic thyroid cancer were enrolled. All 7 patients had V600E mutations. One complete response and one partial response was observed, for a response rate of 29%.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01524978" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 26287849 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Panitumumab", "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6123", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib", "Panitumumab", "Trametinib" ], "phenotypes": null, "pub_med_references": [ 29431699 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Adenocarcinoma", "doid": "0050861", "drug_interaction_type": "Combination", "drugs": [ "Panitumumab", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6124", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "In this trial, 142 patients with metastatic, BRAF V600E mutant colorectal cancer were randomized to receive either BRAF inhibitor dabrafenib (D) + EGFR inhibitor panitumumab (P); or a triple therapy of D + P and MEK inhibition with trametinib (T) or T + P. Confirmed response rates for D+P (n=20), D+T+P (n=91), and T+P (n=31) were 10%, 21%, and 0%, respectively.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Panitumumab", "Trametinib" ], "phenotypes": null, "pub_med_references": [ 29431699 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6178", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 792 (91%) patients had V600E, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 150/397 patients (38%) in the treatment group and 229/395 patients (58%) in the placebo group for a 95% CI Hazard Ratio of 0.48 (0.39-0.58).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01682083" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 28891408 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6938", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response. The hazard ratio for progression or death in the V600E group was 0.81 for dabrafenib-trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-trametinib group, 68% of patients had a response, which was 15 percentage points higher than in the dabrafenib-alone group (95% CI, 4 to 24; P=0.006).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01584648" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 25265492 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6940", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this Phase I and II study (NCT01072175) patients with metastatic melanoma were given dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy. From V600E patients, 45 received monotherapy and 92 received combination therapy. Hazard ratio for progression or death was 0.43 (95% CI, 0.27-0.71). Both patients with the BRAF V600E and V600K mutation showed significant improvement in progression-free survival.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01072175" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 23020132 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Anaplastic Thyroid Carcinoma", "doid": "0080522", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/6975", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Interim analysis of a basket trial evaluating the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in previously treated V600E-mutated patients showed 11/16 patients with anaplastic thyroid carcinoma responded to treatment (overall response rate 69%; 95% CI, 41% to 89%). Seven patients had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached after 120 weeks.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02034110" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 29072975 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7156", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Patients with completely resected colorectal adenocarcinoma (Stage II-III) were treated with fluorouracil and leucovorin +/- ironotecan. Of the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall survival, but not for relapse-free survival, in patients with stages II and III combined, and in stage III alone. For all MSI low and stable tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95% CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40, P=0.0069). The authors note prognostic value for BRAF V600E, especially in non-MSI high tumors.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 20008640 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7157", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "The CRYSTAL Phase III Trial evaluated efficacy of irinotecan, fluorouracil, and leucovorin (FOLFIRI) with or without Cetuximab for colorectal cancer patients who presented with unresectable metastatic disease. BRAF mutation status (V600E) was analyzed via LightMix BRAF V600E Kit. V600E mutations were detected in 60/999 tumor samples (6%), 59 of which were wild-type for KRAS. When comparing patients with wildtype KRAS (n=625), BRAF V600E tumors had worse outcomes relative to BRAF wildtype. For patients with BRAF V600E tumors (n=566), median overall survival (OS) was 25.1 months with cetuximab and 21.6 months without cetuximab. For patients with wildtype BRAF (n=59), median OS was 14.1 months with cetuximab and 10.3 months without cetuximab.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 21502544 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Childhood Low-grade Glioma", "doid": "0080830", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7191", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Using Sanger sequencing, BRAFV600E mutations were identified in 21 of 285 patients with PLGGs (7.4%). This mutation was enriched in hemispheric tumors (p<0.007) and was associated with shorter progression-free survival (p=0.011) and overall survival (p=0.032) [mt (n=18) vs wt (n=166)].", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": [ "Pediatric onset", "Early young adult onset" ], "pub_med_references": [ 29948154 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": { "asco_citation_id": "168986", "asco_abstract_id": "688" }, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Cetuximab", "Encorafenib", "Binimetinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7260", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a phase III trial, patients with BRAF V600E mutated metastatic colorectal cancer received triplet combination with encorafenib + binimetinib + cetuximab in a second or third-line setting. In the safety-lead in part of this trial, 30 patients were given triplet therapy, of which 29 with V600E mutation were included in the efficacy analysis. The objective response rate was 48% [95%CI: 29.4 - 67.5], median PFS was 8.0 mo [95%CI: 5.6 - 9.3], and median OS was 15.3 mo [95%CI: 9.6 - not reached]. The author concluded that triplet therapy was well tolerated and PFS and OS were substantially improved over historical standard of care.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02928224" ], "normalized_drug": [ "Binimetinib", "Cetuximab", "Encorafenib" ], "phenotypes": null, "pub_med_references": null, "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": { "asco_citation_id": "169315", "asco_abstract_id": "187" }, "clinical_significance": "Sensitivity/Response", "disease": "Biliary Tract Cancer", "doid": "4607", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7264", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In a phase II trial, 33 patients with advanced or metastatic biliary tract cancer (BTC) received dabrafenib (D) and trametinib (T) in a second or higher line therapeutic context. Of the 33 patients, 30 had BRAF V600E mutated tumors, and 32 were evaluable. Objective response rate was 41% (13/32; 95% CI, 24 - 59%). Median PFS was 7.2 months (95% CI, 4.6 - 10.1 months), and median OS was 11.3 months (95% CI, 7.3 - 17.6 months). The author concluded that D+T therapy should be considered for patients with BRAF V600E mutated BTC.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02034110" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": null, "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Langerhans Cell Sarcoma", "doid": "7146", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7583", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Off-label use of vemurafenib to treat BRAF V600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. Fifty-four patients from 12 countries were treated with vemurafenib 20 mg/kg/day. Because LCH is a heterogeneous systemic disease, the quantitative Disease Activity Score (DAS), which reflects overall LCH extension, was used as an evaluation criterion. At 8 weeks, 38 patients had CRs (non-active disease) and 16 had PRs (active disease better). DAS decreased from a median value of 7 to 0 between VMF initiation and day 60 (P < 0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 31513482 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Encorafenib", "Binimetinib", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/7612", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "665 patients with BRAF V600E-mutated metastatic CRC were enrolled In this open-label, phase 3 trial. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (triplet group vs. control P<0.001). The median progression-free survival in the triplet-therapy group was 4.3 months (95% CI, 4.1 to 5.2) and 1.5 months (95% CI, 1.5 to 1.7) in the control group (hazard ratio for disease progression or death, 0.38; 95% CI, 0.29 to 0.49; P<0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02928224" ], "normalized_drug": [ "Binimetinib", "Cetuximab", "Encorafenib" ], "phenotypes": null, "pub_med_references": [ 31566309 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Irinotecan", "Cetuximab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/8506", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Irinotecan, cetuximab and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 250% increased lifespan (ILS) compared to vehicle treated controls. Of the ten treated mice, nine experienced partial response and one experienced a complete response. Compared to all doublet and single agent combinations of vemurafenib, irinotecan, and cetuximab, triplet therapy produced the best TGI and ILS (p<0.05, p <0.0001 for all comparisons).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Cetuximab", "Irinotecan", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22180495 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Vemurafenib", "Erlotinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/8507", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "This in vivo study examined the efficacy of various treatments on athymic nude mice xenografted with colorectal cancer HT29 cells, which harbor BRAF V600E. The authors sought to understand whether the addition of vemurafenib (a BRAF V600E inhibitor) to agents approved for the treatment of metastatic colorectal cancer increased therapeutic efficacy, and which combinations worked best. Erlotinib and vemurafenib combination therapy resulted in >100% tumor growth inhibition (TGI) and 142% increased lifespan (ILS) compared to vehicle treated controls. Of ten treated mice, 9 experienced partial response. Doublet therapy produced a greater increase in TGI and ILS than either agent in isolation.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": [ "Erlotinib", "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 22180495 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9018", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Open label phase 2 (Clinical Level B) trial including patients from across the globe (USA, Italy, and the Netherlands) investigating sensitivity to Vemurafenib in patients that have BRAF V600E-positive papillary thyroid cancer that have become resistant to radioactive iodine (the standard treatment). There were 116 patients identified for this trial, 51 of which met the conditions to be included. These 51 patients were split into two cohorts: 1) patients that had never been treated with a multikinase inhibitor targeting VEGFR and 2) patients that have previously been treated with a VEGFR multikinase inhibitor. In cohort 1, ten of 26 patients had best overall response. Best overall response was defined as the proportion of patients with a complete or partial response, however these ten patients were all partial response. In the same cohort 1, nine had achieved stable disease control for at least six months; therefore, 19 patients achieved disease control (73% of total cohort 1, 95% CI 52-88). In cohort 2, of 23 eligible patients, six had a partial response as best overall response and six had stable disease control for at least six months; therefore, 12 patients achieved disease control. (55% of total cohort 2, 95% CI 32-76). The authors conclude that vemurafenib is a potential treatment option for late-stage BRAF V600E-positive papillary thyroid cancer for treatment in patients naïve to a multikinase inhibitor (Cohort 1) and to patients that have been previously treated with a multikinase inhibitor (Cohort 2).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT01286753" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 27460442 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Poor Outcome", "disease": "Papillary Thyroid Carcinoma", "doid": "3969", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9170", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Clinical study including 219 patients with papillary thyroid cancer (PTC) to determine a correlation between the BRAF V600E mutation and poor oncological outcome. This study found that 107 of the 219 (49%) patients had this mutation signifying that the BRAF V600E mutation is one of the most commonly occurring among PTC patients. This cohort was split into two groups—BRAF+ and BRAF-. Of the 107 patients that were BRAF+, 25% had tumor reoccurrence compared with 9% in the BRAF- group (P=0.004). Multivariate analysis was performed to assess BRAF correlation independent of known contributing factors to cancer such as age, gender, and multifocality. The results showed that the BRAF mutation is indicative/contributes to lymph node metastasis, associated with tumor reoccurrence, stage, and that recurrent disease was more extensive and required more aggressive treatments in BRAF+ patients compared with BRAF- patients. The authors conclude that PTC patients with the BRAF V600E mutation have worse clinicopathological outcomes, and that the BRAF mutation can be used to assess risk stratification in patients with PTC.", "evidence_status": "accepted", "evidence_type": "Prognostic", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 16174717 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Colorectal Cancer", "doid": "9256", "drug_interaction_type": "Combination", "drugs": [ "Cetuximab", "Encorafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/9851", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "The open-label phase 3 BEACON CRC trial included 665 patients with BRAF V600E-mutated metastatic CRC. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI. The median overall survival was 8.4 months (95% CI, 7.5 to 11.0) in the doublet-therapy group and 5.4 months (95% CI, 4.8 to 6.6) in the control group, with a significantly lower risk of death compared to the control group (hazard ratio for death doublet-group vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group, 20% in the doublet-therapy group (95% CI 13 to 29) and 2% (95% CI, 0 to 7) in the control group (doublet group vs. control P<0.001). Median PFS was 4.2 months (95% CI, 3.7 to 5.4) in the doublet-therapy group, and 1.5 months (95% CI, 1.5 to 1.7) in the control group (hazard ratio for disease progression doublet-group vs control, 0.40; 95% CI, 0.31 to 0.52, P<0.001).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2023-01-09 21:46:25 UTC", "nct_ids": [ "NCT02928224" ], "normalized_drug": [ "Cetuximab, Encorafenib" ], "phenotypes": null, "pub_med_references": [ 31566309 ], "rating": "5", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Cancer", "doid": "162", "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/11672", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "This NCI-MATCH trial was conducted in 35 patients of which 29 were included in the primary efficacy analysis with tumors with BRAF V600E mutations, and treated with a combination of dabrafenib and trametinib. The ORR was 37.9% (90% CI, 22.9-54.9). The median PFS and median OS were 11.4 months (90% CI, 8.4-16.3) and 28.6 months respectively. Meaningful results were achieved with this treatment with an overall DCR of 75.9%.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2024-01-22 16:58:55 UTC", "nct_ids": null, "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 32758030 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Low Grade Glioma", "doid": "0080829", "drug_interaction_type": null, "drugs": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/11770", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "In this trial, 19 patients with pediatric brain tumours (1 patient with Astrocytoma, 1 with Fibrillary Astrocytoma, 10 with Pilocytic Astrocytoma, 5 with Ganglioglioma and 2 with Pleomorphic Xanthoastrocytoma) harbouring BRAF V600E were treated with vemurafenib. The study reported a positive response to the treatment, with 1 complete response, 5 partial responses, and 13 patients with stable disease.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2024-03-25 21:25:38 UTC", "nct_ids": [ "NCT01748149" ], "normalized_drug": [ "Vemurafenib" ], "phenotypes": null, "pub_med_references": [ 32523649 ], "rating": "3", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Solid Tumor", "doid": null, "drug_interaction_type": "Combination", "drugs": [ "Dabrafenib", "Trametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/12161", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "In this trial, patients with advanced rare tumours harbouring BRAF V600E mutations were treated with a combination of dabrafenib and trametinib. The study included eight distinct cohorts: anaplastic thyroid carcinoma (ATC) (n=36), biliary tract cancer (BTC)(n=43), gastrointestinal stromal tumour (GIST) (n=1), adenocarcinoma of the small intestine (ASI) (n=3), low-grade glioma (LGG) (n=13), high-grade glioma (HGG)(n=45), hairy cell leukemia(HCL) (n=55), and multiple myeloma (MM)(n=19). The overall response rates for these cohorts were 56%, 53%, 0%, 67%, 54%, 33%, 89%, and 50% respectively. The median duration of response varied, with 14.4 months for anaplastic thyroid carcinoma, 8.9 months for biliary tract cancer, 7.7 months for adenocarcinoma of the small intestine, 31.2 months for high-grade glioma, and 11.1 months in multiple myeloma. In the remaining cohorts, the duration of response was not reached. Progression-free survival was measured at 6.7 months for ATC, 9.0 months for BTC, 9.5 months for ASI, 5.5 months for HGG, and 6.3 months for MM. PFS could not be evaluated in the LGG and HCL groups due to small patient numbers. The overall survival was 14.5 months for ATC, 13.5 months for BTC, 17.6 months for HGG, 21.8 months for ASI, and 33.9 months for MM cohorts. OS could not be evaluated for the LGG and HCL groups due to a low number of deaths. Adverse events were reported in 97.6% of the patients (n=201), with 87.9% (n=181) of these being related to the study treatment. Serious adverse events occurred in 45.1% (n=93) of patients across all cohorts.", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2025-01-24 17:19:02 UTC", "nct_ids": [ "NCT02034110" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 37059834 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null }, { "asco_entry": null, "clinical_significance": "Sensitivity/Response", "disease": "Low Grade Glioma", "doid": "0080829", "drug_interaction_type": "Combination", "drugs": [ "Trametinib", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/12162", "evidence_direction": "Supports", "evidence_level": "A", "evidence_statement": "In this trial, patients with pediatric (age <18 years) low-grade gliomas harbouring BRAF V600E (n=49), were treated with either trametinib monotherapy (n=13) or dabrafenib + trametinib (n=36). In patients treated with trametinib monotherapy, 15% (95% CI, 1.9-45.4; n=2) had objective PRs, and 46% (n=6) had stable disease for 12 or more weeks after the first dose of therapy. The estimated 24-month duration of response (DOR) was 100%. The median PFS was 16.4 months (95% CI, 3.2 to NR). In patients treated with a combination of trametinib and dabrafenib 25% (95% CI, 12.1-42.2; n=9) had objective PRs and 64% (n=23) experienced stable disease. The median DOR was 33.6 months (95% CI, 11.2 - NR), while the 24-month DOR was 80% (95% CI, 30-100). The median PFS was 36.9 months (95% CI, 36.0 - NR).", "evidence_status": "accepted", "evidence_type": "Predictive", "gene": "BRAF", "gene_civic_url": null, "last_review_date": "2025-01-13 16:55:37 UTC", "nct_ids": [ "NCT02124772" ], "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 36375115 ], "rating": "4", "representative_transcript": "ENST00000288602.6", "transcripts": null, "variant": "V600E", "variant_civic_url": "https://civicdb.org/links/variants/12", "variant_origin": "Somatic", "variant_summary": null, "assertion_details": null, "civic_variant_evidence_score": null, "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": null } ] } ], "saphetor_known_pathogenicity": [ { "version": "28-Jan-2026", "items": [ { "annotations": { "NCBI ClinVar2": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", 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"codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 29271794 ], "id": 5415, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 30824584 ], "pathogenicity": "DR", "id": 5306, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 30220966 ], "pathogenicity": "DR", "id": 4851, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 12068308 ], "pathogenicity": "P", "id": 3477, "confirmedByFunctionalStudy": false }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 21134544 ], "pathogenicity": "P", "id": 29985, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 22549559 ], "pathogenicity": "DA", "id": 25543, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 25815361 ], "pathogenicity": "P", "id": 17830, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 21412762 ], "pathogenicity": "RF", "id": 17395, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 24531980 ], "pathogenicity": "P", "id": 14021, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 27923714 ], "pathogenicity": "P", "id": 12262, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" }, { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "pub_med_references": [ 27554081 ], "id": 6791, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr7:140753336 A⇒T" } ], "UNIPROT UniProt Variants": [ { "functions": [ "coding" ], "coding_impact": "missense", "acmg_confirmed": true, "acmg_class": "Pathogenic", "acmg_reannotated": "Pathogenic", "source": "UNIPROT UniProt Variants", "codon": 600, "gene_symbol": "BRAF", "hgvs": "V600E", "transcript": "NM_004333.6", "possible_functional_studies": [ 17374713, 22281684, 23263490 ], "pub_med_references": [ 22281684, 23263490, 23302800, 23685455, 24455489, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "disease_name": [ "Adenomas and Adenocarcinomas", "Adenomas and Adenocarcinomas", "Adenomas and Adenocarcinomas", "Adenomas and Adenocarcinomas", "Adenomas and Adenocarcinomas" ], "annotation_id": "VAR_018629" } ] } } ] } ], "alpha_missense": [ { "version": "03-Jul-2024", "main_data": "Likely Pathogenic", "alpha_missense_score": 0.9926908169804987 } ], "acmg_annotation": { "version_name": "13.14.1", "gene_symbol": "BRAF", "transcript": "NM_004333.6", "transcript_reason": "MANE select", "coding_impact": "missense", "blosum_score": -5, "verdict": { "ACMG_rules": { "benign_score": 0, "benign_subscore": "Uncertain Significance", "clinical_score": 5.261, "pathogenic_score": 11, "pathogenic_subscore": "Pathogenic", "total_score": 11, "verdict": "Pathogenic" }, "classifications": [ "PS3", "PM1", "PM5", "PP5_Moderate", "PM2_Supporting" ] }, "classifications": [ { "name": "PS3", "met_criteria": true, "user_explain": [ "Combined evidence strength is Strong (score = 4). .", "Moderate: ClinVar classifies this variant as Uncertain Significance but a number of high confidence submitters have classified as Likely Pathogenic and Pathogenic, 1 star (reviewed Dec '25, 45 submissions of which 2 are from high confidence submitters), backed by functional studies (requires user validation) mentioned in 2 articles (%%PUBMED:22281684%% and %%PUBMED:17374713%%), and also citing 11 articles (%%PUBMED:34476331%%, %%PUBMED:31891627%%, %%PUBMED:29925953%%, %%PUBMED:28854169%%, %%PUBMED:25950823%%, and 6 more).", "Supporting: UniProt Variants classifies this variant as Pathogenic, backed by functional studies (requires user validation) mentioned in 3 articles (%%PUBMED:23263490%%, %%PUBMED:22281684%%, and %%PUBMED:17374713%%), and also citing 9 articles (%%PUBMED:29925953%%, %%PUBMED:28854169%%, %%PUBMED:25079330%%, %%PUBMED:24717435%%, %%PUBMED:24670642%%, and 4 more).", "Supporting: a VarSome user has classified this variant as Pathogenic, confirmed by a functional study, mentioned in %%PUBMED:18287029%%." ] }, { "name": "PM1", "met_criteria": true, "user_explain": [ "Hot-spot of length 17 amino-acids has 46 missense/in-frame variants (37 pathogenic variants, 9 uncertain variants, and no benign), which qualifies as strong pathogenic.", "UniProt protein BRAF_HUMAN domain 'Protein kinase' has 290 missense/in-frame variants (132 pathogenic variants, 157 uncertain variants, and 1 benign variant), which qualifies as moderate pathogenic.", "Limiting strength to Moderate due to co-occurrence with other predictive evidence." ] }, { "name": "PM5", "met_criteria": true, "user_explain": [ "Alternative variant ##chr7:140453137 C⇒T## (Val600Met) is classified Likely Pathogenic, 1 star, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr7:140453137 C⇒G## (Val600Leu) is classified Pathogenic, 2 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr7:140453137 C⇒A## (Val600Leu) is classified Likely Pathogenic, 1 star, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr7:140453136 A⇒C## (Val600Gly) is classified Pathogenic, 3 stars, by ClinVar (confirmed using the germline classifier).", "4 pathogenic alternative variants identified.", "Limiting strength to Moderate due to co-occurrence with other predictive evidence." ] }, { "name": "PP5", "met_criteria": true, "user_explain": [ "Moderate: the VarSome community has classified this variant as Pathogenic, citing 68 articles (%%PUBMED:33188936%%, %%PUBMED:32305313%%, %%PUBMED:32291725%%, %%PUBMED:31602213%%, %%PUBMED:30892822%%, and 63 more)." ], "strength": "Moderate" }, { "name": "PM2", "met_criteria": true, "user_explain": [ "Variant not found in gnomAD genomes, good gnomAD genomes coverage = 30.6.", "GnomAD exomes allele count = 1 is less than 5 for AD gene BRAF, good gnomAD exomes coverage = 82.5." ], "strength": "Supporting" } ], "gene_id": 2273, "sample_findings": { "phenotypes": "No matching phenotype found for gene BRAF which is associated with Cardiofaciocutaneous Syndrome, Cardiofaciocutaneous Syndrome 1, Colorectal Cancer, Craniopharyngioma, and 16 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype.", "mode_of_inheritance": "AD, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, and gene2phenotype." } }, "amp_annotation": { "version_name": "13.14.1", "verdict": { "tier": "Tier I", "approx_score": 3.345 }, "classifications": [ { "name": "Crtd", "tier": "Tier I", "user_explain": { "Tier I": [ "Melanoma, Bowel Cancer, Langerhans Cell Histiocytosis, Pilocytic Astrocytoma, and 16 more, 13 therapies (Dabrafenib + Trametinib, Vemurafenib, Cobimetinib + Vemurafenib, Dabrafenib, and 9 more), sensitive, actionable, diagnostic, and prognostic, FDA-approved, FDA or Standard Care, Clinical Evidence, and curated, from OncoKB and CIViC, citing %%PUBMED:39863775%%, %%PUBMED:37978284%%, %%PUBMED:37733309%%, %%PUBMED:37270692%%, and 78 more. No patient information was provided to match the cancer." ], "Tier II": [ "Bowel Cancer, Melanoma, Anaplastic Thyroid Cancer, Cancer, and 18 more, 25 therapies (Vemurafenib, Dabrafenib + Trametinib, Dabrafenib + Trametinib + Vemurafenib, Bevacizumab + Capecitabine + Vemurafenib, and 21 more), actionable, prognostic, and diagnostic, Clinical Evidence, case reports, pre-clinical, and curated, from CIViC, citing %%PUBMED:37059834%%, %%PUBMED:36375115%%, %%PUBMED:32758030%%, %%PUBMED:32523649%%, and 52 more. No patient information was provided to match the cancer." ], "Tier III": [ "Bowel Cancer, Melanoma, Hairy Cell Leukemia, and Plasma Cell Myeloma, 4 therapies (Vemurafenib, Dactolisib + Selumetinib, Panitumumab + Vemurafenib, and Pictilisib), actionable, case reports, pre-clinical, and Clinical Evidence, from CIViC, citing %%PUBMED:29320312%%, %%PUBMED:27325282%%, %%PUBMED:26678033%%, %%PUBMED:26352686%%, and 3 more. No patient information was provided to match the cancer.", "Variant not found in CKB." ] }, "approx_score": 9.0 }, { "name": "Drug", "tier": "Tier I", "user_explain": { "Tier I": [ "13 therapies (Dabrafenib + Trametinib, Vemurafenib, Cobimetinib + Vemurafenib, Dabrafenib, and 9 more), Sensitive, Actionable, Diagnostic, and Prognostic, FDA-approved, FDA or Standard Care, Clinical Evidence, and curated, from OncoKB and CIViC. Citing %%PUBMED:39863775%%, %%PUBMED:37978284%%, %%PUBMED:37733309%%, %%PUBMED:37270692%%, and 78 more. Related to Melanoma, Bowel Cancer, Langerhans Cell Histiocytosis, Pilocytic Astrocytoma, and 16 more. No patient information was provided to match the cancer." ], "Tier II": [ "25 therapies (Vemurafenib, Dabrafenib + Trametinib, Dabrafenib + Trametinib + Vemurafenib, Bevacizumab + Capecitabine + Vemurafenib, and 21 more), Actionable, Prognostic, and Diagnostic, Clinical Evidence, case reports, pre-clinical, and curated, from CIViC. Citing %%PUBMED:37059834%%, %%PUBMED:36375115%%, %%PUBMED:32758030%%, %%PUBMED:32523649%%, and 52 more. Related to Bowel Cancer, Melanoma, Anaplastic Thyroid Cancer, Cancer, and 18 more. No patient information was provided to match the cancer." ], "Tier III": [ "Searches for drugs or clinical trials are disabled because there is Tier I curated drug evidence for this variant.", "4 therapies (Vemurafenib, Dactolisib + Selumetinib, Panitumumab + Vemurafenib, and Pictilisib), Actionable, case reports, pre-clinical, and Clinical Evidence, from CIViC. Citing %%PUBMED:29320312%%, %%PUBMED:27325282%%, %%PUBMED:26678033%%, %%PUBMED:26352686%%, and 3 more. Related to Bowel Cancer, Melanoma, Hairy Cell Leukemia, and Plasma Cell Myeloma. No patient information was provided to match the cancer." ] }, "approx_score": 8.0 }, { "name": "Germ", "tier": "Tier I", "user_explain": { "Tier I": [ "This missense variant is classified Pathogenic by the germline classifier, using rules PS3, PM1, PM5, PP5_Moderate, and PM2_Supporting." ] }, "approx_score": 7.0 }, { "name": "Path", "tier": "Tier II", "user_explain": { "Tier II": [ "GHR reports that the BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. Also, associates BRAF with the following 8 cancers: Cholangiocarcinoma, Erdheim-Chester Disease, Gastrointestinal Stromal Tumor, Langerhans Cell Histiocytosis, Large Congenital Melanocytic Nevus, and 3 more.", "Mondo associates gene BRAF with the following 11 cancers: Colorectal Cancer, Craniopharyngioma, Cushing Disease due to Pituitary Adenoma, Differentiated Thyroid Carcinoma, Hairy Cell Leukemia, and 6 more.", "The Human Protein Atlas classifies BRAF as an oncogene." ] }, "approx_score": 6.0 }, { "name": "Pubs", "tier": "Tier I", "user_explain": { "Tier I": [ "VarSome users have linked 75 articles stating the variant is pathogenic (%%PUBMED:40291070%%, %%PUBMED:39333321%%, %%PUBMED:38269481%%, %%PUBMED:37296851%%, %%PUBMED:37231247%%, and 70 more) (6 by VarSome curation team)(7 entries have been automatically lifted over from hg38)." ] }, "approx_score": 5.0 }, { "name": "Soma", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is reported in 4 904 out of the 4 506 somatic samples for gene BRAF, which has 2 555 reported somatic variants. Its GnomAD ƒ = 0.00000398. This is statistically rated Tier I." ], "Tier III": [ "CBioPortal reports 4 073 samples, cancer type = 1 193 x Melanoma, 905 x Thyroid Cancer, 789 x Colorectal Cancer, and 32 more, sample type = 1 632 x Primary, 1 411 x Metastasis, 56 x Primary Tumor, and 8 more, tissue = 1 187 x Skin, 921 x Thyroid, 867 x Bowel, and 21 more, citing 98 articles (%%PUBMED:30770838%%, %%PUBMED:30089490%%, %%PUBMED:29043205%%, %%PUBMED:28607096%%, %%PUBMED:28556791%%, and 93 more).", "CancerHotspots reports 831 samples, bio-type = 1 x protein_coding, cancer type = 315 x Thyroid Cancer, 311 x Melanoma, 109 x Colorectal Cancer, and 18 more, tissue site = 315 x Thyroid, 311 x Skin, 113 x Bowel, and 15 more, citing %%PUBMED:26513174%%.", "Variant not found in GDC or ICGC." ] }, "total_samples": 4904, "approx_score": 4.0 }, { "name": "Freq", "tier": "Tier II", "user_explain": { "Tier II": [ "Variant not found in gnomAD genomes, good gnomAD genomes coverage = 30.6.\nGnomAD exomes allele count = 1 is less than 5 for AD gene BRAF, good gnomAD exomes coverage = 82.5." ] }, "approx_score": 3.0 }, { "name": "Type", "tier": "Tier III", "user_explain": { "Tier III": [ "No relevant information.", "Variant is not predicted splicing: no prediction from MaxEntScan." ] }, "approx_score": 2.0 }, { "name": "Pred", "tier": "Tier III", "user_explain": { "Tier III": [ "No relevant information." ] }, "approx_score": 1.0 } ], "sample_findings": { "sex": "47.1% of samples across somatic databases are male", "age": "Patient's age, 47, is close to the average of 53. 17.8% are between 40-50.", "age_match": "True" } }, "cbio_portal": [ { "version": "06-Jun-2023", "total_samples": 4073, "sample_id": null, "sample_type": [ { "key": "Primary", "value": 1632 }, { "key": "Metastasis", "value": 1411 }, { "key": "Primary Tumor", "value": 56 }, { "key": "Recurrence", "value": 13 }, { "key": "Metastatic", "value": 6 }, { "key": "Local Recurrence", "value": 5 }, { "key": "Recurrent", "value": 4 }, { "key": "Relapse", "value": 2 }, { "key": "First Recurrence", "value": 1 }, { "key": "Second Recurrence", "value": 1 }, { "key": "Tumor Primary", "value": 1 } ], "study_name": null, "mutation_status": [ { "key": "Somatic", "value": 2234 }, { "key": "Somatic_Vs_Pool", "value": 1 } ], "validation_status": [ { "key": "Untested", "value": 74 }, { "key": "Valid", "value": 37 }, { "key": "Validated", "value": 4 }, { "key": "High", "value": 2 }, { "key": "Invalid", "value": 1 }, { "key": "Not_Done", "value": 1 } ], "center": [ { "key": "Mskcc", "value": 1377 }, { "key": "Broad.Mit.Edu", "value": 1021 }, { "key": "Dfci.Harvard.Edu", "value": 112 }, { "key": "Bergerlab", "value": 59 }, { "key": "Msk-Impact", "value": 43 }, { "key": "Yale.Edu", "value": 23 }, { "key": "Hgsc.Bcm.Edu", "value": 21 }, { "key": "Discover.Nci.Nih.Gov", "value": 11 }, { "key": "University Of Michigan", "value": 7 }, { "key": "Msk-Impact410", "value": 6 }, { "key": "Papaemmanuil_Nejm_2016", "value": 5 }, { "key": "Genentech", "value": 4 }, { "key": "Ut Southwestern", "value": 3 }, { "key": "Mdanderson.Org/Ucsc.Edu/Broad.Mit.Edu", "value": 3 }, { "key": "Ucsf", "value": 2 }, { "key": "Ucsc.Edu/Broad.Mit.Edu", "value": 2 }, { "key": "Omrf.Org", "value": 2 }, { "key": "Msk-Impact468", "value": 2 }, { "key": "Msk-Impact410+Idtcustom_18_20161108", "value": 1 }, { "key": "Www.Unioviedo.Es/Iuopa/", "value": 1 }, { "key": "Ohsu.Edu", "value": 1 }, { "key": "Mskcc-Cmo", "value": 1 }, { "key": "Msk-Impact341+Chi-Solit", "value": 1 }, { "key": "Bc", "value": 1 }, { "key": "Msk-Hemepact_V3", "value": 1 }, { "key": "Metabric", "value": 1 }, { "key": "John_Hopkins", "value": 1 }, { "key": "Inserm.Fr", "value": 1 }, { "key": "Hgsc.Bcm.Edu;Broad.Mit.Edu;Ucsc.Edu;Bcgsc.Ca", "value": 1 }, { "key": "Hgsc.Bcm.Edu;Broad.Mit.Edu", "value": 1 }, { "key": "Gr", "value": 1 } ], "t_ref_count": 901758, "t_alt_count": 388092, "n_ref_count": 636283, "n_alt_count": 589, "n_depth": 48829, "t_depth": 77325, "canonical": true, "hotspot": false, "ensp": 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"LightSalmon", "id": 792, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Langerhans Cell Histiocytosis", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" } }, { "abstracts": [], "alterations": [ "V600E" ], "description": "", "level_of_evidence": "LEVEL_Dx3", "pmids": [ "25422482", "26637772" ], "tumor_type": { "children": {}, "code": "ECD", "color": "LightSalmon", "id": 854, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Erdheim-Chester Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" } }, { "abstracts": [], "alterations": [ "V600E" ], "description": "", "level_of_evidence": "LEVEL_Dx2", "pmids": [ "23347903", "25480661", "22072557", "21910720", "22210875", "25120816", "22028477", "21663470", "26071465", "22531170" ], "tumor_type": { "children": {}, "code": "HCL", "color": "LimeGreen", "id": 962, "level": 5, "main_type": { "id": null, "name": "Mature B-Cell Neoplasms", "tumor_form": "LIQUID" }, "name": "Hairy Cell Leukemia", "parent": "MBN", "tissue": "Lymphoid", "tumor_form": "LIQUID" } }, { "abstracts": [], "alterations": [ "Oncogenic Mutations" ], "description": "", "level_of_evidence": "LEVEL_Dx3", "pmids": [ "22237106" ], "tumor_type": { "children": {}, "code": "ETPLL", "color": "LimeGreen", "id": 757, "level": 4, "main_type": { "id": null, "name": "T-Lymphoblastic Leukemia/Lymphoma", "tumor_form": "LIQUID" }, "name": "Early T-Cell Precursor Lymphoblastic Leukemia", "parent": "TLL", "tissue": "Lymphoid", "tumor_form": "LIQUID" } } ], "diagnostic_summary": "", "gene_exist": true, "gene_summary": "BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.", "highest_diagnostic_implication_level": "LEVEL_Dx2", "highest_fda_level": "LEVEL_Fda2", "highest_prognostic_implication_level": null, "highest_resistance_level": null, "highest_sensitive_level": "LEVEL_1", "hotspot": true, "last_update": "02/05/2025", "mutation_effect": { "citations": { "abstracts": [], "pmids": [ "25417114", "20179705", "23833300", "26091043", "26343582", "12068308", "30351999", "25079552", "28783719", "19251651", "15035987" ] }, "description": "The class I activating exon 15 BRAF V600E mutation is located in the kinase domain of the BRAF protein and is highly recurrent in melanoma, lung and thyroid cancer, among others (PMID: 28783719, 26091043, 25079552, 23833300, 25417114, 28783719, 12068308). This mutation has been comprehensively biologically characterized and has been shown to activate the downstream MAPK pathway independent of RAS (PMID: 15035987, 12068308, 19251651, 26343582), to render BRAF constitutively activated in monomeric form (PMID: 20179705), and to retain sensitivity to RAF monomer inhibitors such as vemurafenib and dabrafenib (PMID:26343582, 28783719, 20179705, 30351999).", "knowneffect": "Gain-of-function" }, "oncogenic": "Oncogenic", "other_significant_resistance_levels": null, "other_significant_sensitive_levels": null, "prognostic_implications": null, "prognostic_summary": "", "query": { "id": null, "referencegenome": "GRCh37", "hugosymbol": "BRAF", "canonicaltranscript": null, "entrezgeneid": 673, "alterationtype": null, "alteration": "V600E", "tumortype": null, "proteinend": null, "consequence": null, "hgvs": null, "svtype": null, "hgvsinfo": null, "proteinstart": null }, "treatments": [ { "abstracts": [], "alterations": [ "V600E" ], "description": "Dabrafenib is an orally bioavailable RAF inhibitor that is FDA-approved for use in patients with BRAF V600E- and V600K-mutant metastatic melanoma. FDA approval is based on the randomized Phase III trial in which dabrafenib (150 mg orally twice daily) was compared with dacarbazine (1000 mg/m2 intravenously every three weeks) in 250 patients with BRAF V600E-mutated metastatic melanoma. Dabrafenib was associated with improved progression-free survival (median 5.1 months vs. 2.7 months with dacarbazine; hazard ratio = 0.30, p<0.0001) (PMID: 22735384). Dabrafenib may also be effective against brain metastases, as demonstrated by a Phase II trial in which approximately 40% of previously untreated and 30% of previously treated patients experienced an overall intracranial response and a separate trial in which nine out of ten patients had a reduction in the size of their brain metastases (PMID: 23051966, 22608338).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "22608338", "23051966", "22735384" ] }, { "abstracts": [ { "abstract": "Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020.", "link": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318" }, { "abstract": "Bouffet et al. Abstract# LBA2002, ASCO 2022.", "link": "https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA2002" } ], "alterations": [ "V600E" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved in combination for the treatment of patients with solid tumors other than colorectal harboring BRAF V600E mutation. FDA approval was based on data from 131 adult patients with solid tumors treated with dabrafenib and trametinib in the BRF117019 and NCI-MATCH trials and 36 pediatric patients treated with dabrafenib and trametinib in the CTMT212X2101 study. Of the 131 adult patients treated with dabrafenib and trametinib, the overall response rate was 41% (54/131; 95% CI = 33-50) and of the 36 pediatric patients treated with dabrafenib and trametinib (low-grade glioma, n=34; high-grade glioma, n=2), the overall response rate was 25% (95% CI = 12-24) (PMID: 32818466, 34838156, 32758030)(Abstract: Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318/) In the randomized, Phase II study of dabrafenib and trametinib in 110 patients with BRAF V600–mutant pediatric low-grade glioma (dabrafenib + trametinib treatment, n=37; carboplatin + vincristine treatment, n=37), the overall response rate was 47% (95% CI= 35%-59%) with dabrafenib and trametinib and 11% (95% CI= 3%-25%) with carboplatin and vincristine, and the progression-free survival was 20.1 months (95% CI= 12.8 mo-not estimable) with dabrafenib and trametinib and 7.4 months (95% CI= 3.6-11.8 mo) with carboplatin and vincristine (Abstract: Bouffet et al. Abstract# LBA2002, ASCO 2022. https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA2002) FDA approval was supported by results in COMBI-d, COMBI-v and BRF113928 studies in melanoma and lung cancer (PMID: 23020132, 25399551, 27283860).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "", "id": 5, "level": -1, "main_type": { "id": null, "name": "All Solid Tumors", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "", "tumor_form": "SOLID" }, "pmids": [ "32758030", "27283860", "23020132", "32818466", "25399551", "34838156" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved alone or in combination for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. FDA approval was based on results of the Phase II study of dabrafenib combined with trametinib in patients with BRAF V600E-positive ATC in which the overall response rate in sixteen evaluable patients was 69% (11/16; 95% CI= 41%-89%)(PMID: 29072975).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "THAP", "color": "Teal", "id": 297, "level": 2, "main_type": { "id": null, "name": "Thyroid Cancer", "tumor_form": "SOLID" }, "name": "Anaplastic Thyroid Cancer", "parent": "THYROID", "tissue": "Thyroid", "tumor_form": "SOLID" }, "pmids": [ "29072975" ] }, { "abstracts": [ { "abstract": "Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020.", "link": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318" } ], "alterations": [ "V600E" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved in combination for the treatment of patients with solid tumors other than colorectal harboring BRAF V600E mutation. FDA approval was based on data from 131 adult patients with solid tumors treated with dabrafenib and trametinib in the BRF117019 and NCI-MATCH trials and 36 pediatric patients treated with dabrafenib and trametinib in the CTMT212X2101 study. Of the 131 adult patients treated with dabrafenib and trametinib, the overall response rate was 41% (54/131; 95% CI = 33-50) and of the 36 pediatric patients treated with dabrafenib and trametinib (low-grade glioma, n=34; high-grade glioma, n=2), the overall response rate was 25% (95% CI = 12-24) (PMID: 32818466, 34838156, 32758030)(Abstract: Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318/) Approval was supported by results in COMBI-d, COMBI-v and BRF113928 studies in melanoma and lung cancer (PMID: 23020132, 25399551, 27283860). In the Phase II ROAR basket trial of dabrafenib + trametinib in patients with BRAF V600E-mutated rare cancers (biliary tract cancer, n=43), the overall response rate was 53%, the median progression-free survival was nine months (95% CI = 5.5, 9.4) and the median overall survival was 13.5 months (95% CI = 10.4, 17.6) (PMID: 37059834). Of the 43 patients with biliary tract cancer, 53% of patients (23/43) had a partial response and 37% (16/43) had stable disease (PMID: 37059834). Additionally, in subprotocol H of the NCI-MATCH basket trial of dabrafenib + trametinib in patients with BRAF V600E-mutant solid tumors (n=4 patients with intrahepatic cholangiocarcinoma), the overall response rate was 100%, with 4/4 patients achieving a partial response (PMID: 32758030).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "BILIARY_TRACT", "color": "Green", "id": 153, "level": 1, "main_type": { "id": null, "name": "Biliary Tract Cancer", "tumor_form": "SOLID" }, "name": "Biliary Tract", "parent": "TISSUE", "tissue": "Biliary Tract", "tumor_form": "SOLID" }, "pmids": [ "32758030", "37059834", "27283860", "23020132", "32818466", "25399551", "34838156" ] }, { "abstracts": [ { "abstract": "Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020.", "link": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318" } ], "alterations": [ "V600E" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved in combination for the treatment of patients with solid tumors other than colorectal harboring BRAF V600E mutation. FDA approval was based on data from 131 adult patients with solid tumors treated with dabrafenib and trametinib in the BRF117019 and NCI-MATCH trials and 36 pediatric patients treated with dabrafenib and trametinib in the CTMT212X2101 study. Of the 131 adult patients treated with dabrafenib and trametinib, the overall response rate was 41% (54/131; 95% CI = 33-50) and of the 36 pediatric patients treated with dabrafenib and trametinib (low-grade glioma, n=34; high-grade glioma, n=2), the overall response rate was 25% (95% CI = 12-24) (PMID: 32818466, 34838156, 32758030)(Abstract: Bouffet et al. Abstract# LGG-49, Neuro-Oncology 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715318/) Approval was supported by results in COMBI-d, COMBI-v and BRF113928 studies in melanoma and lung cancer (PMID: 23020132, 25399551, 27283860). In the Phase II ROAR basket trial of dabrafenib + trametinib in patients with BRAF V600E-mutated rare cancers (biliary tract cancer, n=43), the overall response rate was 53%, the median progression-free survival was nine months (95% CI = 5.5, 9.4) and the median overall survival was 13.5 months (95% CI = 10.4, 17.6) (PMID: 37059834). Of the 43 patients with biliary tract cancer, 53% of patients (23/43) had a partial response and 37% (16/43) had stable disease (PMID: 37059834). Additionally, in subprotocol H of the NCI-MATCH basket trial of dabrafenib + trametinib in patients with BRAF V600E-mutant solid tumors (n=4 patients with intrahepatic cholangiocarcinoma), the overall response rate was 100%, with 4/4 patients achieving a partial response (PMID: 32758030).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "MIXED", "id": 63, "level": 0, "main_type": { "id": null, "name": "Hepatobiliary Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "MIXED", "tumor_form": "SOLID" }, "pmids": [ "32758030", "37059834", "27283860", "23020132", "32818466", "25399551", "34838156" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Dabrafenib, a small molecule RAF inhibitor, and trametinib, a small molecule MEK1/2 inhibitor, are FDA-approved in combination for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. FDA approval is based on the results of the Phase II Study CDRB436G2201 (NCT02684058) of dabrafenib plus trametinib versus carboplatin plus vincristine in 110 patients with BRAF V600-mutant LGG, as assessed by local or central laboratory tests. In the Phase II Study CDRB436G2201 (NCT02684058), the dabrafenib plus trametinib cohort (n=73 [n=70, V600E; n=3, other]) demonstrated an overall response rate (ORR) of 47% (95% CI=35-59), with a 3% (n=2) complete response (CR) rate, a 44% (n=32) partial response (PR) rate and a 41% (n=30) stable disease (SD) rate, and a median duration of response (DOR) of 20.3 months (95% CI=12.0-NE) while the chemotherapy cohort (n=37 [n=35, V600E; n=1, other; n=1, nonmutant]) demonstrated an ORR of 11% (95% CI=3-25) (OR=7.19 [95% CI=2.30-22.40]; RR=4.31 [95% CI=1.70-11.20]; p<0.001), with a 3% (n=1) CR rate, an 8% (n=3) PR rate and a 41% (n=15) SD rate, and a median DOR that was not estimable (95% CI=6.6-NE) (PMID: 37733309).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "LGGNOS", "color": "Gray", "id": 646, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Low-Grade Glioma, NOS", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "37733309" ] }, { "abstracts": [], "alterations": [ "V600E", "V600K" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved alone or in combination for the treatment of patients with metastatic melanoma harboring a V600E or V600K BRAF mutation. FDA approval of dabrafenib in combination with trametinib was based on results from an open-label Phase III study of combination therapy versus dabrafenib monotherapy in 247 patients with metastatic melanoma who were naive to treatment with BRAF inhibitors. Combined dabrafenib and trametinib, administered in full monotherapy doses, improved the response rate in patients with BRAF V600-mutant metastatic melanoma versus dabrafenib monotherapy (67% vs.51%; p<0.002). However, median progression-free survival improved by only 2 weeks (9.3 months vs 8.8 months; HR = 0.75) compared with dabrafenib monotherapy (PMID: 23020132). Combination therapy is associated with less cutaneous toxicity than monotherapy, but systemic toxicity may be increased (PMID: 25287827, 25399551). Follow-up trials have demonstrated that all clinical measures inclusive of overall and median progression-free survival as well as objective response rates, median duration of response and number of patients with complete response favored patients treated with combination dabrafenib and trametinib, administered in full monotherapy doses, compared to either dabrafenib or vemurafenib monotherapy, including patients who previously progressed on BRAF inhibitor monotherapy (PMID: 25287827, 25399551, 25265492). Additionally, patients with melanoma treated with dabrafenib and trametinib in both the neoadjuvant and adjuvant settings have improved survival over patients given standard of care (PMID: 29361468, 28991513, 28891408). Promising clinical data has also suggested that addition of an immunotherapy agent to combination RAF and MEK inhibitor treatment may improve rate of overall response and duration of response in melanoma patients (PMID: 31171876, 31171879, 31171878).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "31171876", "28891408", "31171878", "31171879", "25265492", "25287827", "29361468", "28991513", "23020132", "25399551" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved alone or in combination for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. FDA approval was based on a Phase II, multicenter, non-randomized, open-label study of dabrafenib in combination with trametinib in patients with chemotherapy-pretreated, metastatic, stage IV BRAF(V600E)-mutant non-small cell lung cancer, in which 36 of 57 patients (63%) achieved overall tumor response, with two patients experiencing durable complete responses and 34 patients having durable partial responses (PMID: 27283860). In the third arm of that study, which included patients with untreated, metastatic, stage IV BRAF(V600E)-mutant non-small cell lung cancer, 23 of 26 patients (64%, 95% CI 46-79) had an overall response, with two patients (6%) having durable complete response and 21 (58%) having partial response (PMID: 28919011).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" }, { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "Gainsboro", "id": 102, "level": 0, "main_type": { "id": null, "name": "Non-Small Cell Lung Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Lung", "tumor_form": "SOLID" }, "pmids": [ "28919011", "27283860" ] }, { "abstracts": [], "alterations": [ "V600E", "V600K" ], "description": "The combination of encorafenib, an inhibitor of V600E- or V600K-mutant BRAF, and binimetinib, an inhibitor of MEK1/2, is FDA-approved in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. FDA approval was based on the results of the Phase III COLUMBUS trial of combined encorafenib plus binimetinib versus single-agent vemurafenib in 577 patients with BRAF V600E- or V600K-mutant metastatic melanoma in which the median progression-free survival was 14.9 months (95% CI = 11.0-18.5) in the encorafenib plus binimetinib group versus 7.3 months (95% CI = 5.6-8.2) in the single agent vemurafenib group (HR= 0.54, 95% CI = 0.41-0.71; p<0·0001) (PMID: 29573941). In the five-year update of the Phase III COLUMBUS trial, the progression-free survival and overall survival were 23% and 35% respectively in the encorafenib plus binimetinib group (n=192) versus 10% and 21% respectively in the single agent vemurafenib group (n=191), and the median duration of response and disease control rate were 18.6 months and 92.2% in the encorafenib plus binimetinib group versus 12.3 months and 81.2% in the single-agent vemurafenib group (PMID: 35862871).", "approved_indications": [], "drugs": [ { "drug_name": "Encorafenib", "ncit_code": "C98283" }, { "drug_name": "Binimetinib", "ncit_code": "C84865" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "29573941", "35862871" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Encorafenib, a small molecule inhibitor of RAF kinases, and binimetinib, a small molecule inhibitor of MEK1/2 kinases, are FDA-approved in combination for the treatment of patients with BRAF V600E mutant non-small cell lung cancer (NSCLC). FDA approval was based on the Phase II, open-label, multicenter, single-arm PHAROS study of encorafenib in combination with binimetinib in treatment-naïve (n=59) and previously treated (n=39) patients with BRAF V600E-mutant metastatic NSCLC (PMID: 37270692). In the Phase II PHAROS study, the objective response rate and duration of response for treatment-naïve patients were 72% (95% CI=62, 85) and 44 months (95% CI=23.1, NE), with 15% experiencing a complete response and 59% experiencing a partial response, compared to 46% (95% CI=30, 63) and 18 months (95% CI=7.4, NE) in previously treated patients, with 10% experiencing a complete response and 36% experiencing a partial response (PMID: 37270692).", "approved_indications": [], "drugs": [ { "drug_name": "Encorafenib", "ncit_code": "C98283" }, { "drug_name": "Binimetinib", "ncit_code": "C84865" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "Gainsboro", "id": 102, "level": 0, "main_type": { "id": null, "name": "Non-Small Cell Lung Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Lung", "tumor_form": "SOLID" }, "pmids": [ "37270692" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Encorafenib, a small molecule RAF-targeted inhibitor, and cetuximab, an anti-EGFR antibody, are FDA-approved in combination for the treatment of adult patients with metastatic CRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. BRAF V600E mutations for treatment with encorafenib plus cetuximab were detected by the FoundationOne Liquid CDx, the MI Cancer Seek assay or the therascreen BRAF V600E RGQ PCR Kit. FDA approval was based on results of the Phase III BEACON (NCT02928224) study of encorafenib plus cetuximab (n=220) versus triplet treatment (including a MEK1/2 inhibitor) versus chemotherapy (n=221) in 665 patients with BRAF V600E-mutant colorectal cancer. \n\nIn the Phase III BEACON (NCT02928224) trial, the overall response rate (complete or partial response) was 20% (95% CI=13-29) in the doublet arm versus 2% (95% CI=<1%-7%) in the chemotherapy arm (n=221), with median overall survival of 8.4 months in the doublet arm (95% CI= 7.5-11.0) and 5.4 months in the chemotherapy arm (95% CI= 4.8-6.6) (PMID: 31566309).", "approved_indications": [], "drugs": [ { "drug_name": "Encorafenib", "ncit_code": "C98283" }, { "drug_name": "Cetuximab", "ncit_code": "C1723" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "31566309" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Encorafenib, a small molecule RAF-targeted inhibitor, and cetuximab, an anti-EGFR antibody, are FDA-approved in combination with FOLFOX6 for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. BRAF V600E mutations were detected by the therascreen BRAF V600E RGQ PCR Kit. FDA approval was based on the results of the Phase III BREAKWATER (NCT04607421) trial of encorafenib plus cetuximab versus encorafenib plus cetuximab with FOLFOX6 versus standard-of-care in 479 patients with BRAF V600E-mutant mCRC.\n\nIn the Phase III BREAKWATER (NCT04607421) trial, the encorafenib plus cetuximab with FOLFOX6 cohort (n=110) demonstrated an overall response rate (ORR) of 60.9% (95% CI=51.6-69.5), with a 2.7% (n=3) complete response (CR) rate, 58.2% (n=64) partial response (PR) rate and 28.2% (n=31) stable disease (SD) rate, and a median duration of response (DOR) of 13.9 months (95% CI=8.5-NE) (PMID: 39863775). The standard-of-care cohort (n=110) demonstrated an ORR of 40.0% (95% CI=31.3-49.3) (odds ratio=2.443 [95% CI=1.403-4.253; 99.8% CI=1.019-5.855]; p=0.0008), with a 1.8% (n=2) CR rate, 38.2% (n=42) PR rate and 30.9% (n=34) SD rate, and a median DOR of 11.1 months (95% CI=6.7-12.7) (PMID: 39863775).", "approved_indications": [], "drugs": [ { "drug_name": "Encorafenib", "ncit_code": "C98283" }, { "drug_name": "Cetuximab", "ncit_code": "C1723" }, { "drug_name": "FOLFOX Regimen", "ncit_code": "C11197" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "39863775" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Tovorafenib is an orally available, pan-RAF small molecule inhibitor that is FDA-approved for the treatment of pediatric patients six months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. FDA approval was based on the results of the Phase II FIREFLY-1 (NCT04775485) trial of tovorafenib in 76 patients (median age=8 years old [range=2-21]) with relapsed or refractory pediatric LGG harboring an activating BRAF alteration based on local laboratory testing. In the Phase II FIREFLY-1 (NCT04775485) trial, the overall RAPNO-LGG cohort demonstrated an objective response rate (ORR) of 51% (95% CI=40-63), with a 37% (n=28) partial response rate and 14% (n=11) minor response rate, a median duration of response (DOR) of 13.8 months (95% CI=11.3-NE) in 39 patients and a median progression-free survival of 13.8 months (95% CI=8.3-16.9) (PMID: 37978284). The BRAF V600E mutation subcohort (n=12) demonstrated an ORR of 50% (95% CI=21-79) and a median DOR that was not evaluable (95% CI=8.4-NE) (PMID: 37978284).", "approved_indications": [], "drugs": [ { "drug_name": "Tovorafenib", "ncit_code": "C106254" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "LGGNOS", "color": "Gray", "id": 646, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Low-Grade Glioma, NOS", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "37978284" ] }, { "abstracts": [], "alterations": [ "V600E", "V600K" ], "description": "Trametinib is an oral small molecule inhibitor of MEK1/2 that is FDA-approved alone or with dabrafenib for the treatment of patients with metastatic melanoma harboring a V600E or V600K BRAF mutation. In an open-label, randomized Phase III trial, patients with BRAF V600E/K-mutated unresectable, metastatic melanoma received oral trametinib (2 mg once daily) or an intravenous regimen of either dacarbazine (1000 mg/m2) or paclitaxel (175 mg/m2) every three weeks. Trametinib demonstrated improved progression-free survival (HR for disease progression or death = 0.45) and six-month overall survival (81% vs. 67%; death HR = 0.54; p=0.01) (PMID: 22663011). However, like other MEK inhibitors, the benefit of trametinib is limited by adverse reactions, most notably grade three or four rash and diarrhea (PMID: 22663011). Trametinib is not typically used as monotherapy for patients with BRAF V600K melanoma given its lower response rate compared to BRAF inhibitors and combined BRAF and MEK inhibitors. Patients previously treated with a RAF inhibitor appear to be less likely than untreated patients to respond to trametinib treatment (PMID: 22663011), and FDA guidelines state that trametinib as a monotherapy is not indicated for these patients. Dabrafenib and trametinib are FDA-approved as a combination therapy, which has superior clinical outcomes compared to dabrafenib or trametinib monotherapy (PMID: 25399551, 25265492). Additionally, patients with melanoma treated with dabrafenib and trametinib in both the neoadjuvant and adjuvant settings had improved survival over patients given standard of care (PMID: 29361468).", "approved_indications": [], "drugs": [ { "drug_name": "Trametinib", "ncit_code": "C77908" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "29361468", "25399551", "22663011", "25265492" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Vemurafenib is an orally available, small molecule RAF-targeted inhibitor that is FDA-approved for the treatment of patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. FDA approval was based on the results of the Phase II VE-BASKET (NCT01524978) trial of vemurafenib in 26 patients with BRAF V600-mutant non-melanoma cancers (n=22, ECD; n=4, Langerhans cell histiocytosis [LCH]).\nIn the Phase II VE-BASKET (NCT01524978) trial, the ECD cohort demonstrated an overall response rate of 54.5% (12/22) (95% CI=32.2-75.6), with one patient (4.5%) achieving complete response and eleven patients (50%) achieving partial response, and the median progression-free survival and overall survival were not reached (PMID: 29188284, 26287849).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "ECD", "color": "LightSalmon", "id": 854, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Erdheim-Chester Disease", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "26287849", "29188284" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Vemurafenib is an orally available kinse inhibitor of V600-mutant BRAF that is FDA-approved for treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation. Vemurafenib has been shown to have nearly equivalent activity against melanomas with BRAF V600E and V600K mutations (PMID: 24508103). In a randomized Phase III trial comparing vemurafenib (960 mg orally twice daily) with dacarbazine (1000 mg/m2 i.v. every 3 weeks) for treatment-naive, metastatic, BRAF V600E-mutant melanoma, vemurafenib was associated with better overall survival (median survival 13.6 months vs. 9.7 months; hazard ratio 0.70, p=.0008) and longer median progression-free survival (6.9 months vs. 1.6 months) (PMID: 24508103). Final overall survival data from the BRIM-3 study showed that the survival advantage of vemurafenib over dacarbazine persisted through the 4-year landmark, with survival rates for vemurafenib and dacarbazine at the 4-year landmark being 17.0% and 15.6%, respectively (PMID: 28961848). However, a trial evaluating clinical outcomes in patients with melanoma treated with either combination therapy of dabrafenib and trametinib compared to those treated with vemurafenib monotherapy demonstrated improved survival outcomes in the combination-therapy group compared to the vemurafenib group (PMID: 25399551).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "28961848", "24508103", "25399551" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "The combination of vemurafenib, an inhibitor of V600-mutant BRAF, and cobimetinib, an inhibitor of MEK1/2, with atezolizumab, an immunotherapeutic PD-L1 antibody, is FDA-approved for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. FDA approval was based on the results of the Phase III double-blind, randomized, placebo-controlled IMspire150 trial of Atezolizumab + Cobimetinib + Vemurafenib versus Placebo + Cobimetinib + Vemurafenib in 514 patients with BRAF V600-mutant melanoma in which the median progression-free survival was 15.1 mos (95% CI=11.4,18.4) in the triplet arm versus 10.6 mos (95% CI=9.3,12.7) in the doublet + placebo arm (HR=0.78; 95% CI= 0.63, 0.97; p=0.0249) (PMID: 32534646).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Atezolizumab", "ncit_code": "C106250" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "32534646" ] }, { "abstracts": [], "alterations": [ "V600E", "V600K" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for the treatment of patients with BRAF V600-mutant metastatic or unresectable locally advanced melanoma. FDA approval was based on results from the randomized Phase III coBRIM trial of combined vemurafenib and cobimetinib versus vemurafenib and placebo in 495 patients with metastatic BRAF V600-mutant melanoma that demonstrated superior clinical benefit measures in the combination versus the control arm. Specifically, median progression-free survival was 9.9 months in the combination arm versus 6.2 months in the control arm (HR = 0.51), with a complete response rate of 10% versus 4%, respectively, and interim nine-month overall survival of 81% versus 73%, respectively (PMID: 25265494). Follow-up analysis of the coBRIM trial showed two-year overall survival was 48.3% in the combination group versus 38.0% in the monotherapy group (PMID: 27480103), and five-year followup of the BRIM7 study showed a median overall survival of 31.8 months and a five-year survival rate of 39.2% (PMID: 31732523).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_1", "level_associated_cancer_type": { "children": {}, "code": "MEL", "color": "Black", "id": 257, "level": 2, "main_type": { "id": null, "name": "Melanoma", "tumor_form": "SOLID" }, "name": "Melanoma", "parent": "SKIN", "tissue": "Skin", "tumor_form": "SOLID" }, "pmids": [ "27480103", "31732523", "25265494" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Encorafenib, a small molecule inhibitor of RAF kinase, and panitumumab, an antibody that targets EGFR, are NCCN-compendium listed in combination as level 2A therapy for patients with BRAF V600E-positive colorectal cancer. In the Phase III BEACON study of encorafenib + cetuximab, another EGFR antibody, versus triplet treatment (including a MEK1/2 inhibitor) versus chemotherapy in 665 patients with BRAF V600E-mutant colorectal cancer, the overall response rate (complete or partial response) was 20% (95% CI= 13-29) in the doublet arm (n=220) versus 2% (95% CI= <1%-7%) in the chemotherapy arm (n=221), with median overall survival of 8.4 months in the doublet arm (95% CI= 7.5-11.0) and 5.4 months in the control arm (95% CI= 4.8-6.6) (PMID: 31566309). Panitumumab has also been used in doublet and triplet combination therapy, with a response rate in one study of 26% (PMID: 29431699).", "approved_indications": [], "drugs": [ { "drug_name": "Encorafenib", "ncit_code": "C98283" }, { "drug_name": "Panitumumab", "ncit_code": "C1857" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "", "color": "SaddleBrown", "id": 40, "level": 0, "main_type": { "id": null, "name": "Colorectal Cancer", "tumor_form": "SOLID" }, "name": "", "parent": null, "tissue": "Bowel", "tumor_form": "SOLID" }, "pmids": [ "29431699", "31566309" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Selumetinib is a small molecule tyrosine kinase inhibitor of MEK1/2. In stratum one of the phase II PBTC study of selumetinib in 25 patients with pilocytic astrocytoma harboring a KIAA1549–BRAF fusion or BRAF V600E mutation, seven of eighteen patients with a KIAA1549–BRAF fusion had a partial response to treatment (PMID: 31151904). Additionally, the two year progression-free survival rate for the BRAF study population (n=25) was 70% (95% CI = 47–85) (PMID: 31151904).", "approved_indications": [], "drugs": [ { "drug_name": "Selumetinib", "ncit_code": "C66939" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "PAST", "color": "Gray", "id": 452, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Pilocytic Astrocytoma", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "31151904" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "Vemurafenib is an orally available kinse inhibitor of V600-mutant BRAF that is FDA-approved for treatment of patients with various BRAF V600-harboring tumors, including melanoma and Edheim-Chester Disease (ECD). Vemurafenib is listed as a 2A therapeutic in the NCCN guidelines for Hairy Cell Leukemia (HCL) based on data from two Phase II trials. In one study of vemurafenib in patients with BRAF V600E-mutant HCL (n=24), the overall response rate was 100%, with 42% of patients (10 of 24) having complete responses, with a response duration of 11.7 months and one year progression free and overall survival rates of 73% and 91%, repectively (PMID: 26352686). In another study of vemurafenib in patients with BRAF V600E-mutant HCL (n=26), the overall response rate was 96%, with 35% of patients (9 of 26) having complete responses (PMID: 26352686).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" } ], "fda_level": "LEVEL_Fda2", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "HCL", "color": "LimeGreen", "id": 962, "level": 5, "main_type": { "id": null, "name": "Mature B-Cell Neoplasms", "tumor_form": "LIQUID" }, "name": "Hairy Cell Leukemia", "parent": "MBN", "tissue": "Lymphoid", "tumor_form": "LIQUID" }, "pmids": [ "26352686" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Vemurafenib is an orally available, small molecule RAF-targeted inhibitor that is FDA-approved for the treatment of patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. Vemurafenib and dabrafenib are listed as monotherapies in the NCCN Histiocytic Neoplasms Guidelines (V3.2024) under the section \"Principles of Systemic Therapy\" as recommended treatment regimens for patients with Langerhans cell histiocytosis (LCH) harboring BRAF V600E mutations. NCCN recommendation was based on the results of the Phase II VE-BASKET (NCT01524978) and case reports.\nIn the Phase II VE-BASKET (NCT01524978) trial, all four patients of the LCH cohort achieved partial response (PMID: 29188284). In the case series evaluating the use of BRAF inhibitors in six adult patients with BRAF V600E‐mutant LCH, patients treated with vemurafenib monotherapy (n=3) achieved one complete response (CR), one partial response (PR) and one stable disease (SD) response while patients treated with dabrafenib monotherapy (n=3) achieved one CR and two PRs (PMID: 32985015). In a separate case report, a patient with BRAF V600E-mutant LCH was treated with dabrafenib plus trametinib and demonstrated a sustained metabolic response (PMID: 30154124).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "LCH", "color": "LightSalmon", "id": 792, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Langerhans Cell Histiocytosis", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "32985015", "29188284", "30154124" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for patients with BRAF V600E-positive melanoma, non-small cell lung cancer, and anaplastic thyroid cancer, and is NCCN-listed for patients with low-grade glioma, anaplastic glioma, and glioblastoma. Patients with various glioma subtypes harboring BRAF V600E mutations have shown responses to RAF and MEK inhibition. Three out of five patients with anaplastic astrocytoma had a response (one partial response, two stable disease) to vemurafenib monotherapy (PMID: 30351999). One patient with high-grade glioma (NOS) had stable disease in response to vemurafenib monotherapy (PMID:30351999). Four out of eight patients with glioma (NOS) had a response (one partial response, three stable disease, two progressive disease, two not evaluable) to vemurafenib monotherapy (PMID: 26287849). One patient with anaplastic oligoastrocytoma had stable disease in response to vemurafenib monotherapy (PMID: 30462564). Four of seven patients with glioblastoma multiforme had a response (one complete response, three stable disease, one progressive disease, two not evaluable) to vemurafenib monotherapy (PMID: 30351999, 24725538). Four patients with glioblastoma (including epithelioid glioblastoma) had a response (one “near-complete” response, three stable disease) to either dabrafenib monotherapy (n=2) or vemurafenib monotherapy (n=2) (PMID: 29621181, 29039591, 33117675, 34232949).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "DIFG", "color": "Gray", "id": 284, "level": 2, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Diffuse Glioma", "parent": "BRAIN", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "24725538", "29039591", "30462564", "34232949", "29621181", "30351999", "26287849", "33117675" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for patients with melanoma, non-small cell lung cancer, and anaplastic thyroid cancer, and is NCCN-listed for patients with low-grade glioma, anaplastic glioma, and glioblastoma. Patients with various glioma subtypes harboring BRAF V600E mutations have shown responses to RAF and MEK inhibition. Six patients with ganglioglioma had a partial response to either vemurafenib monotherapy (n=2), vemurafenib + cobimetinib (n=1), or dabrafenib monotherapy (n=3)(PMID: 25524464, 31985841, 26579623, 31502039). Twelve out of thirteen patients with pleomorphic xanthoastrocytoma had a response (one complete response, one “near-complete” response, six partial response, four stable disease) to either dabrafenib + trametinib (n=2) or vemurafenib monotherapy (n=11) (PMID: 28984141, 26287849, 30351999). Three patients with anaplastic pleomorphic xanthoastrocytoma had a response (one complete response, one “near-complete” response, one partial response) to either vemurafenib monotherapy (n=1) or dabrafenib monotherapy (n=2)(PMID: 25092772, 29039591). One patient with low-grade glioma, NOS had a partial response to dabrafenib monotherapy (PMID: 27398937). Two patients with pilocytic astrocytoma had a response (one partial response, one stable disease) to vemurafenib monotherapy (PMID: 30351999). Three of four patients with anaplastic ganglioglioma had a response (one partial response, one \"significant response\", one stable disease, one not evaluable) to either dabrafenib + trametinib (n=1) or vemurafenib monotherapy (n=3)(PMID: 29380516, 30351999). One patient with pilomyxoid astrocytoma had a partial response to vemurafenib monotherapy (PMID: 24821190).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "ENCG", "color": "Gray", "id": 277, "level": 2, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Encapsulated Glioma", "parent": "BRAIN", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "25524464", "29039591", "31985841", "25092772", "31502039", "27398937", "29380516", "28984141", "24821190", "30351999", "26579623", "26287849" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for patients with melanoma, non-small cell lung cancer, and anaplastic thyroid cancer, and is NCCN-compendium listed as recommended treatment of central nervous system cancers such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA) and ganglioglioma. In a case series of two patients with BRAF V600E-mutant PXA, combination treatment of dabrafenib with trametinib led to partial responses by RANO criteria in both patients (PMID: 28984141). In a case report of a sixteen-year-old female with BRAF V600E-mutant anaplastic ganglioglioma, dabrafenib and trametinib in combination led to a significant response that was maintained at least six months after treatment initiation (PMID: 29380516). In a separate case report of a 28-year-old man with BRAF V600E-mutant anaplastic ganglioglioma, combination treatment of vemurafenib and cobimetinib led to a complete response after three months, with no evidence of recurrence after sixteen months of treatment (PMID: 30120137).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "PXA", "color": "Gray", "id": 416, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Pleomorphic Xanthoastrocytoma", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "30120137", "29380516", "28984141" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for patients with melanoma, non-small cell lung cancer, and anaplastic thyroid cancer, and is NCCN-compendium listed as recommended treatment of central nervous system cancers such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA) and ganglioglioma. In a case series of two patients with BRAF V600E-mutant PXA, combination treatment of dabrafenib with trametinib led to partial responses by RANO criteria in both patients (PMID: 28984141). In a case report of a sixteen-year-old female with BRAF V600E-mutant anaplastic ganglioglioma, dabrafenib and trametinib in combination led to a significant response that was maintained at least six months after treatment initiation (PMID: 29380516). In a separate case report of a 28-year-old man with BRAF V600E-mutant anaplastic ganglioglioma, combination treatment of vemurafenib and cobimetinib led to a complete response after three months, with no evidence of recurrence after sixteen months of treatment (PMID: 30120137).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "GNG", "color": "Gray", "id": 609, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Ganglioglioma", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "30120137", "29380516", "28984141" ] }, { "abstracts": [], "alterations": [ "V600E" ], "description": "The RAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib is FDA-approved for patients with melanoma, non-small cell lung cancer, and anaplastic thyroid cancer, and is NCCN-compendium listed as recommended treatment of central nervous system cancers such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma (PXA) and ganglioglioma. In a case series of two patients with BRAF V600E-mutant PXA, combination treatment of dabrafenib with trametinib led to partial responses by RANO criteria in both patients (PMID: 28984141). In a case report of a sixteen-year-old female with BRAF V600E-mutant anaplastic ganglioglioma, dabrafenib and trametinib in combination led to a significant response that was maintained at least six months after treatment initiation (PMID: 29380516). In a separate case report of a 28-year-old man with BRAF V600E-mutant anaplastic ganglioglioma, combination treatment of vemurafenib and cobimetinib led to a complete response after three months, with no evidence of recurrence after sixteen months of treatment (PMID: 30120137).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" }, { "drug_name": "Cobimetinib", "ncit_code": "C68923" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "PAST", "color": "Gray", "id": 452, "level": 3, "main_type": { "id": null, "name": "Glioma", "tumor_form": "SOLID" }, "name": "Pilocytic Astrocytoma", "parent": "ENCG", "tissue": "CNS/Brain", "tumor_form": "SOLID" }, "pmids": [ "30120137", "29380516", "28984141" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Vemurafenib is an orally available, small molecule RAF-targeted inhibitor that is FDA-approved for the treatment of patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. Vemurafenib and dabrafenib are listed as monotherapies in the NCCN Histiocytic Neoplasms Guidelines (V3.2024) under the section \"Principles of Systemic Therapy\" as recommended treatment regimens for patients with Langerhans cell histiocytosis (LCH) harboring BRAF V600E mutations. NCCN recommendation was based on the results of the Phase II VE-BASKET (NCT01524978) and case reports.\nIn the Phase II VE-BASKET (NCT01524978) trial, all four patients of the LCH cohort achieved partial response (PMID: 29188284). In the case series evaluating the use of BRAF inhibitors in six adult patients with BRAF V600E‐mutant LCH, patients treated with vemurafenib monotherapy (n=3) achieved one complete response (CR), one partial response (PR) and one stable disease (SD) response while patients treated with dabrafenib monotherapy (n=3) achieved one CR and two PRs (PMID: 32985015). In a separate case report, a patient with BRAF V600E-mutant LCH was treated with dabrafenib plus trametinib and demonstrated a sustained metabolic response (PMID: 30154124).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_2", "level_associated_cancer_type": { "children": {}, "code": "LCH", "color": "LightSalmon", "id": 792, "level": 4, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "Langerhans Cell Histiocytosis", "parent": "HDCN", "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "32985015", "29188284", "30154124" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Vemurafenib is an orally available, small molecule RAF-targeted inhibitor that is FDA-approved for the treatment of patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. Vemurafenib and dabrafenib are listed as monotherapies in the NCCN Histiocytic Neoplasms Guidelines (V3.2024) under the section \"Principles of Systemic Therapy\" as recommended treatment regimens for patients with ECD and Langerhans cell histiocytosis (LCH) harboring BRAF V600E mutations. There is promising clinical data to support the use of vemurafenib and dabrafenib as monotherapies in patients with non-ECD and non-LCH BRAF V600-mutant histiocytic neoplasms.\nIn a case study, a patient with heterozygous BRAF V600E-mutant histiocytic sarcoma was treated with vemurafenib and maintained both clinical and radiologic tumor responses for three months until disease progression (PMID: 25209580). In a second case study, a patient with BRAF V600E-mutant histiocytic sarcoma was treated with vemurafenib plus chemotherapy, antibiotics and steroids and remained in complete remission eighteen months after treatment initiation (PMID: 31376203). In a third case study, a pediatric patient with BRAF V600E-mutant mixed systemic Rosai-Dorfman-Destombes disease and LCH reported sustained clinical and radiographic responses after treatment with dabrafenib prior to disease relapse at thirteen months (PMID: 31213430).", "approved_indications": [], "drugs": [ { "drug_name": "Vemurafenib", "ncit_code": "C64768" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "LightSalmon", "id": 29, "level": 0, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "", "parent": null, "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "31376203", "31213430", "25209580" ] }, { "abstracts": [], "alterations": [ "V600" ], "description": "Vemurafenib is an orally available, small molecule RAF-targeted inhibitor that is FDA-approved for the treatment of patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. Vemurafenib and dabrafenib are listed as monotherapies in the NCCN Histiocytic Neoplasms Guidelines (V3.2024) under the section \"Principles of Systemic Therapy\" as recommended treatment regimens for patients with ECD and Langerhans cell histiocytosis (LCH) harboring BRAF V600E mutations. There is promising clinical data to support the use of vemurafenib and dabrafenib as monotherapies in patients with non-ECD and non-LCH BRAF V600-mutant histiocytic neoplasms.\nIn a case study, a patient with heterozygous BRAF V600E-mutant histiocytic sarcoma was treated with vemurafenib and maintained both clinical and radiologic tumor responses for three months until disease progression (PMID: 25209580). In a second case study, a patient with BRAF V600E-mutant histiocytic sarcoma was treated with vemurafenib plus chemotherapy, antibiotics and steroids and remained in complete remission eighteen months after treatment initiation (PMID: 31376203). In a third case study, a pediatric patient with BRAF V600E-mutant mixed systemic Rosai-Dorfman-Destombes disease and LCH reported sustained clinical and radiographic responses after treatment with dabrafenib prior to disease relapse at thirteen months (PMID: 31213430).", "approved_indications": [], "drugs": [ { "drug_name": "Dabrafenib", "ncit_code": "C82386" } ], "fda_level": "LEVEL_Fda3", "level": "LEVEL_3A", "level_associated_cancer_type": { "children": {}, "code": "", "color": "LightSalmon", "id": 29, "level": 0, "main_type": { "id": null, "name": "Histiocytosis", "tumor_form": "LIQUID" }, "name": "", "parent": null, "tissue": "Myeloid", "tumor_form": "LIQUID" }, "pmids": [ "31376203", "31213430", "25209580" ] } ], "tumor_type_summary": "", "variant_exist": true, "variant_summary": "The BRAF V600E mutation is known to be oncogenic.", "variant_id": null, "vus": false } ] }