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": "05-Aug-2024", "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": "v8", "items": [ { "GTExJsonData": { "exon_id": "ENSG00000157764.12_16", "exon_number": "16", "expressions": { 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"accessions": [ { "variation_id": 13961, "accession_id": "RCV003458334", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20231224, "review_stars": 1, "diseases": [ { "normalized_disease": [ "Vascular Malformation" ], "symbols": { "medgen": "C0158570", "mondo": "MONDO:0024291" }, "names": [ "Vascular Malformation" ] } ], "review_date": 20231022, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Vascular malformation", "review_status": "criteria provided, single submitter", "submission_description": [], "submissions": [ { "submitter_name": "Clinical Genomics Laboratory, Washington University in St. Louis", "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_status": "criteria provided, single submitter", "submitter_date": 20231212, "review_description": "Pathogenic", "method": "clinical testing", "review_date": 20231022, "origin": "somatic", "diseases": [ { "normalized_disease": [ "Vascular Malformation" ], "names": [ "Vascular Malformation" ] } ], "date_updated": 20231224, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV004176942" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV004018627", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20240501, "review_stars": 1, "diseases": [ { "symbols": { "medgen": "CN230736" }, "names": [ "Cardiovascular Phenotype" ] } ], "review_date": 20220523, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cardiovascular phenotype", "review_status": "criteria provided, single submitter", "submission_description": [], "submissions": [ { "submitter_name": "Ambry Genetics", "submission_description": [ "ASSESSED FOR SOMATIC SAMPLE ONLY. FOR ANY GERMLINE INDICATION, PLEASE REASSESS." ], "review_status": "criteria provided, single submitter", "submitter_date": 20240424, "review_description": "Likely pathogenic", "review_date": 20220523, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "medgen": "CN230736" } } ], "date_updated": 20240501, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV005022010" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV002051586", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20220328, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Lymphangioma" ], "symbols": { "medgen": "C0024221", "mondo": "MONDO:0002013", "human_phenotype_ontology": "HP:0100764" }, "names": [ "Lymphangioma" ] } ], "review_date": 20220209, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lymphangioma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "James Bennett Lab, Seattle Childrens Research Institute", "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_status": "no assertion criteria provided", "submitter_date": 20220325, "review_description": "Pathogenic", "method": "research", "finding": [ { "symbols": { "hp": "HP:0100766" }, "normalized_phenotype": [ "Abnormal Lymphatic Vessel Morphology" ] } ], "review_date": 20220209, "origin": "somatic", "diseases": [ { "symbols": { "hp": "HP:0100764" } } ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV002318371" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000430562", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Plasma Cell Myeloma", "Plasma Cell Neoplasm" ], "normalized_cancer": [ "Plasma Cell Myeloma" ], "symbols": { "orphanet": "85443", "omim": "254500", "medgen": "C0026764", "mesh": "D009101", "mondo": "MONDO:0009693", "human_phenotype_ontology": "HP:0006775" }, "names": [ "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Myeloma", "Plasma Cell Neoplasm", "Multiple Myeloma, Somatic" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20190831, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Multiple myeloma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20190912, "review_description": "Likely pathogenic", "method": "clinical testing", "review_date": 20190831, "origin": "somatic", "diseases": [ { "normalized_disease": [ "Plasma Cell Myeloma" ], "normalized_cancer": [ "Plasma Cell Myeloma" ], "symbols": { "orphanet": "ORPHA29073" }, "names": [ "Plasma Cell Myeloma" ] } ], "date_updated": 20191223, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV001132084" }, { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D009101" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504261" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV001248834", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20200719, "review_stars": 0, "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" ] } ], "review_date": 20190215, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nephroblastoma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Pediatric Oncology, Johns Hopkins University", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20200116, "review_description": "Pathogenic", "method": "clinical testing", "review_date": 20190215, "origin": "somatic", "diseases": [ { "normalized_disease": [ "Kidney Wilms Tumor" ], "normalized_cancer": [ "Wilms' Tumor" ], "names": [ "Kidney Wilms Tumor" ] } ], "date_updated": 20200719, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV001147031" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000417746", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Cutaneous Melanoma", "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ], "normalized_cancer": [ "Skin", "Malignant melanoma, somatic", "Cutaneous Melanoma" ], "symbols": { "medgen": "C0151779", "mesh": "C562393", "mondo": "MONDO:0005012", "human_phenotype_ontology": "HP:0012056" }, "pub_med": [ 24493721 ], "names": [ "Cutaneous Melanoma", "Melanoma, Cutaneous Malignant, Susceptibility to, 1", "Cutaneous Melanoma" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Malignant melanoma of skin", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "C562393" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504257" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000424470", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Head and Neck Squamous Cell Carcinoma" ], "normalized_cancer": [ "Head and Neck Squamous Cell Carcinoma" ], "symbols": { "orphanet": "67037", "omim": "275355", "medgen": "C1168401", "mesh": "D000077195", "mondo": "MONDO:0010150" }, "names": [ "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma", "Head and Neck Squamous Cell Carcinoma" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Squamous cell carcinoma of the head and neck", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "C535575" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504258" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000425166", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "finding": [ { "normalized_phenotype": [ "Brainstem Glioma" ], "symbols": { "medgen": "C0677865", "mondo": "MONDO:0002911", "human_phenotype_ontology": "HP:0010796" }, "names": [ "Childhood Brain Stem Glioma" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Brainstem glioma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "review_date": 20160531, "origin": "somatic", "method": "literature only", "finding": [ { "symbols": { "medgen": "C0677865" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504255" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000425847", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Glioblastoma" ], "symbols": { "medgen": "C0017636", "mesh": "D005909", "mondo": "MONDO:0018177" }, "names": [ "Glioblastoma", "Giant Cell Glioblastoma (Histologic Variant)", "Gliosarcoma (Histologic Variant)" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Glioblastoma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D005909" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504252" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000429915", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Lung Adenocarcinoma", "Lung Cancer" ], "normalized_cancer": [ "Lung Adenocarcinoma In Situ" ], "symbols": { "medgen": "C0152013", "mesh": "D000077192", "mondo": "MONDO:0005061", "human_phenotype_ontology": "HP:0030078" }, "pub_med": [ 23562183, 25311215, 24627688, 29355391, 29398453 ], "names": [ "Lung Adenocarcinoma", "Lung Adenocarcinoma", "Lung Cancer" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lung adenocarcinoma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "C538231" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504264" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000443745", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Colorectal Neoplasm" ], "normalized_cancer": [ "Neoplasm of the large intestine", "Colorectal Neoplasms", "Colorectal neoplasm" ], "symbols": { "medgen": "C0009404", "mesh": "D015179", "mondo": "MONDO:0005335", "human_phenotype_ontology": "HP:0100834" }, "pub_med": [ 23012255 ], "names": [ "Neoplasm Large Intestine", "Colorectal Neoplasms", "Colorectal Neoplasm" ] } ], "review_date": 20160531, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm of the large intestine", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D015179" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000504251" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000440802", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Papillary Renal Cell Carcinoma" ], "normalized_cancer": [ "Papillary Renal Cell Carcinoma" ], "symbols": { "medgen": "C1336078", "mesh": "C538614" }, "names": [ "Papillary Renal Cell Carcinoma" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Papillary renal cell carcinoma, sporadic", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "C538614" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504262" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000435441", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Brain Neoplasm" ], "normalized_cancer": [ "CNS/Brain" ], "symbols": { "medgen": "C0006118", "mesh": "D001932", "mondo": "MONDO:0021211", "human_phenotype_ontology": "HP:0030692" }, "names": [ "Brain Neoplasm", "Brain Neoplasm", "Brain Neoplasm", "Brain Neoplasm" ] } ], "review_date": 20160531, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm of brain", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160531, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D001932" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504256" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000443448", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Neoplasm" ], "normalized_cancer": [ "Neoplasm", "Neoplasms", "Neoplasm (disease)" ], "symbols": { "medgen": "C0027651", "mesh": "D009369", "mondo": "MONDO:0005070", "human_phenotype_ontology": "HP:0006741" }, "pub_med": [ 22918138, 23619274, 34131312 ], "names": [ "Neoplasm", "Neoplasms", "Neoplasm" ], "keyword": "neoplasm" } ], "review_date": 20160513, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20160513, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D009369" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504254" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "variant_id": 10190071404531360004, "accession_id": "RCV000067669", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20131031, "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 ], "review_stars": 0, "diseases": [ { "normalized_disease": [ "Melanoma" ], "normalized_cancer": [ "Melanoma" ], "symbols": { "medgen": "C0025202", "mesh": "D008545", "mondo": "MONDO:0005105", "human_phenotype_ontology": "HP:0007474" }, "pub_med": [ 26389333, 26389258 ], "names": [ "Melanoma" ], "keyword": "Neoplasm" } ], "review_date": 20160310, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Melanoma", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Pathogenic", "method": "literature only", "review_date": 20160310, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D008545" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000504249" }, { "submitter_name": "OMIM", "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." ], "submitter_date": 20220317, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "method": "literature only", "review_date": 20140904, "origin": "somatic", "diseases": [ { "normalized_disease": [ "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ], "normalized_cancer": [ "MELANOMA, MALIGNANT, SOMATIC" ], "names": [ "Melanoma, Cutaneous Malignant, Susceptibility to, 1" ] } ], "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 ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000035247" } ] }, { "variation_id": 13961, "accession_id": "RCV000420614", "clinical_significance": [ "Likely pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Colonic Neoplasm" ], "normalized_cancer": [ "Bowel" ], "symbols": { "medgen": "C0009375", "mesh": "D003110", "mondo": "MONDO:0005401", "human_phenotype_ontology": "HP:0100273" }, "names": [ "Colonic Neoplasm", "Colonic Neoplasms", "Colonic Neoplasm" ] } ], "review_date": 20150714, "review_description": "Likely pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Colonic neoplasm", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Likely pathogenic", "method": "literature only", "review_date": 20150714, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D003110" } } ], "date_updated": 20170308, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV000504260" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000662278", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20180714, "review_stars": 0, "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "review_date": 20150507, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cystic epithelial invagination containing papillae lined by columnar epithelium", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20171127, "review_description": "Pathogenic", "method": "literature only", "review_date": 20150507, "origin": "somatic", "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "date_updated": 20180714, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000784606" }, { "submitter_name": "Yale Center for Mendelian Genomics, Yale University", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20220321, "review_description": "Pathogenic", "method": "literature only", "review_date": 20150507, "origin": "somatic", "diseases": [ { "names": [ "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium" ] } ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV002106413" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000433305", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Lung Carcinoma" ], "normalized_cancer": [ "Lung" ], "symbols": { "medgen": "C0684249", "mondo": "MONDO:0005138" }, "pub_med": [ 23562183, 24846033, 25311215, 24627688, 23667368, 29355391, 29398453, 30813707 ], "names": [ "Lung Carcinoma" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20141002, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lung carcinoma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Pathogenic", "method": "literature only", "review_date": 20141002, "origin": "somatic", "diseases": [ { "symbols": { "omim": "211980" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000504250" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000440540", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Gastrointestinal Stromal Tumor" ], "normalized_cancer": [ "Gastrointestinal Stromal Tumor", "Endometrial Stromal Sarcoma", "Gastrointestinal stroma tumor" ], "symbols": { "orphanet": "44890", "omim": "606764", "medgen": "C0238198", "mesh": "D046152", "mondo": "MONDO:0011719", "human_phenotype_ontology": "HP:0100723" }, "pub_med": [ 22685257, 25394175, 23852704 ], "names": [ "Gastrointestinal Stromal Tumor", "Gastrointestinal Stromal Tumor", "Gastrointestinal Stromal Tumor, Somatic", "Gastrointestinal Stroma Tumor" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20141002, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Gastrointestinal stromal tumor", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Pathogenic", "method": "literature only", "review_date": 20141002, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D046152" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000504248" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000432628", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20170308, "review_stars": 0, "diseases": [ { "normalized_disease": [ "Ovarian Neoplasm" ], "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C0919267", "mesh": "D010051", "mondo": "MONDO:0021068", "human_phenotype_ontology": "HP:0100615" }, "pub_med": [ 19042984, 22964825, 23188549, 33410258, 29450531 ], "names": [ "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasms" ] } ], "review_date": 20141002, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Ovarian neoplasm", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20160718, "review_description": "Pathogenic", "method": "literature only", "review_date": 20141002, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D010051" } } ], "date_updated": 20170308, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000504253" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "variant_id": 10190071404531360004, "accession_id": "RCV000014992", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20130404, "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 ], "review_stars": 0, "diseases": [ { "normalized_disease": [ "Colon Carcinoma", "Malignant Colon Neoplasm" ], "normalized_cancer": [ "Bowel" ], "symbols": { "medgen": "C0699790", "mondo": "MONDO:0002032" }, "pub_med": [ 19042984, 25006736, 17060676, 22138009, 24996433, 22855150, 23012255, 25373533, 23852704, 23429431, 34043773 ], "names": [ "Colon Carcinoma", "Colon Carcinoma", "Malignant Colon Neoplasm" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20140904, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Carcinoma of colon", "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." ], "submissions": [ { "submitter_name": "OMIM", "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." ], "submitter_date": 20220317, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "method": "literature only", "review_date": 20140904, "origin": "somatic", "diseases": [ { "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "COLORECTAL CANCER, SOMATIC" ], "names": [ "Colorectal Cancer" ] } ], "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 ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000035248" } ] }, { "variation_id": 13961, "variant_id": 10190071404531360004, "accession_id": "RCV000022677", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20130404, "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 ], "review_stars": 0, "diseases": [ { "normalized_disease": [ "Nongerminomatous Germ Cell Tumor" ], "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" ], "keyword": "Neoplasm" } ], "review_date": 20140904, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nongerminomatous germ cell tumor", "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." ], "submissions": [ { "submitter_name": "OMIM", "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." ], "submitter_date": 20220317, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "method": "literature only", "review_date": 20140904, "origin": "somatic", "diseases": [ { "normalized_cancer": [ "NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC" ], "names": [ "Nonseminomatous Germ Cell Tumors, Somatic" ] } ], "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 ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000043966" } ] }, { "variation_id": 13961, "variant_id": 10190071404531360004, "accession_id": "RCV000014994", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20130404, "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 ], "review_stars": 0, "diseases": [ { "normalized_cancer": [ "Astrocytoma, low-grade, somatic" ], "symbols": { "medgen": "C2674727" }, "names": [ "Astrocytoma, Low-Grade, Somatic" ] } ], "review_date": 20140904, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Astrocytoma, low-grade, somatic", "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." ], "submissions": [ { "submitter_name": "OMIM", "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." ], "submitter_date": 20220317, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "method": "literature only", "review_date": 20140904, "origin": "somatic", "diseases": [ { "normalized_cancer": [ "ASTROCYTOMA, LOW-GRADE, SOMATIC" ], "names": [ "Astrocytoma, Low-Grade, Somatic" ] } ], "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 ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000035250" } ] }, { "variation_id": 13961, "variant_id": 10190071404531360004, "accession_id": "RCV000014993", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20130404, "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 ], "review_stars": 0, "diseases": [ { "normalized_disease": [ "Thyroid Gland Papillary Carcinoma" ], "normalized_cancer": [ "Papillary Thyroid Cancer" ], "symbols": { "orphanet": "146", "medgen": "C0238463", "mesh": "D000077273", "mondo": "MONDO:0005075", "human_phenotype_ontology": "HP:0002895" }, "pub_med": [ 26389271, 26389258 ], "names": [ "Thyroid Gland Papillary Carcinoma", "Nonmedullary Thyroid Carcinoma, Papillary", "Thyroid Carcinoma, Papillary, Somatic", "Thyroid Gland Papillary Carcinoma" ] } ], "review_date": 20140904, "review_status": "no assertion criteria provided", "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Papillary thyroid carcinoma", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion provided", "submitter_date": 20160718, "review_description": "not provided", "method": "literature only", "review_date": 20160310, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "C536915" } } ], "date_updated": 20170308, "clinical_significance": [ "not provided" ], "accession_id": "SCV000504263" }, { "submitter_name": "OMIM", "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." ], "submitter_date": 20220317, "review_description": "Pathogenic", "review_status": "no assertion criteria provided", "method": "literature only", "review_date": 20140904, "origin": "somatic", "diseases": [ { "normalized_cancer": [ "Papillary Thyroid Cancer" ], "names": [ "Thyroid Carcinoma, Papillary, Somatic" ] } ], "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 ], "date_updated": 20220328, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000035249" } ] }, { "variation_id": 13961, "accession_id": "RCV000080903", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20140117, "review_stars": 2, "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "review_date": 20140711, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND not provided", "review_status": "criteria provided, multiple submitters, no conflicts", "submission_description": [], "submissions": [ { "submitter_name": "Clinical Genetics and Genomics, Karolinska University Hospital", "submission_description": [], "review_status": "criteria provided, single submitter", "submitter_date": 20201126, "review_description": "Pathogenic", "method": "clinical testing", "review_date": 20140711, "origin": "germline", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20201212, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV001450230" }, { "submitter_name": "Eurofins Ntd Llc (ga)", "submission_description": [], "review_status": "criteria provided, single submitter", "submitter_date": 20180919, "review_description": "Pathogenic", "method": "clinical testing", "review_date": 20131008, "origin": "germline", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20150629, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000112810" }, { "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20210331, "review_description": "Uncertain significance", "method": "clinical testing", "origin": "unknown", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210413, "clinical_significance": [ "Uncertain significance" ], "accession_id": "SCV001550994" }, { "submitter_name": "Sylvester Comprehensive Cancer Center, University of Miami", "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_status": "no assertion criteria provided", "submitter_date": 20211006, "review_description": "Pathogenic", "method": "clinical testing", "origin": "somatic", "diseases": [ { "symbols": { "medgen": "CN517202" } } ], "date_updated": 20211016, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV001962698" } ], "variant_id": 10190071404531360004 }, { "variation_id": 13961, "accession_id": "RCV000037936", "clinical_significance": [ "Pathogenic" ], "allele_id": 29000, "date_created": 20130503, "review_stars": 0, "diseases": [ { "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" }, "pub_med": [ 24868098, 24673736, 24627688, 23667368, 30813707 ], "names": [ "Non-Small Cell Lung Carcinoma", "Non-Small Cell Lung Carcinoma" ], "disease_mechanism": "Other" } ], "review_date": 20090529, "review_description": "Pathogenic", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Non-small cell lung carcinoma", "review_status": "no assertion criteria provided", "submission_description": [], "submissions": [ { "submitter_name": "Database of Curated Mutations (DoCM)", "submission_description": [], "review_status": "no assertion provided", "submitter_date": 20160718, "review_description": "not provided", "method": "literature only", "review_date": 20160310, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D002289" } } ], "date_updated": 20170308, "clinical_significance": [ "not provided" ], "accession_id": "SCV000504259" }, { "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "submission_description": [], "review_status": "no assertion criteria provided", "submitter_date": 20190321, "review_description": "Pathogenic", "method": "clinical testing", "review_date": 20090529, "origin": "somatic", "diseases": [ { "symbols": { "mesh": "D002289" } } ], "date_updated": 20150131, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000061601" } ], "variant_id": 10190071404531360004 }, { "variant_id": 10190071404531360004, "submissions": [ { "submitter_name": "GeneReviews", "submission_description": [], "review_status": "no assertion provided", "submitter_date": 20160303, "review_description": "not provided", "method": "literature only", "origin": "somatic", "diseases": [ { "symbols": { "medgen": "C1275081" } } ], "date_updated": 20221001, "clinical_significance": [ "not provided" ], "accession_id": "SCV000264636" } ], "variation_id": 13961, "submission_description": [], "review_status": "no assertion provided", "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cardio-facio-cutaneous syndrome", "review_description": "not 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stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis).", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 20301365 ], "cosmic_study": null } }, { "disease": "Cerebral arteriovenous malformation ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Colonic neoplasm", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Colorectal cancer", "disease_description": "Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Colorectal cancer ", "disease_description": "A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.", "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 12198537, 21917714, 23263490, 24455489 ], "cosmic_study": null } }, { "disease": "Cystic epithelial invagination containing papillae lined by columnar epithelium", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Gastrointestinal stromal tumor", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Glioblastoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Lung adenocarcinoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Lung carcinoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Lymphangioma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Malignant melanoma of skin ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 33651321 ], "cosmic_study": null } }, { "disease": "Malignant neoplastic disease", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 26389204 ], "cosmic_study": null } }, { "disease": "Melanoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 33651321 ], "cosmic_study": null } }, { "disease": "Multiple myeloma ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Neoplasm", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 22918138, 23619274 ], "cosmic_study": null } }, { "disease": "Neoplasm of brain", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Neoplasm of ovary", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Neoplasm of the large intestine", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Nephroblastoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Non-small cell lung carcinoma ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": { "pub_med_references": [ 24673736, 24868098 ], "cosmic_study": null } }, { "disease": "Nongerminomatous germ cell tumor", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Papillary renal cell carcinoma, sporadic", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Papillary thyroid carcinoma", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Squamous cell carcinoma of the head and neck ", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} }, { "disease": "Vascular malformation", "disease_description": null, "disease_symbol": null, "disease_alt_symbol": null, "evidences": {} } ], "siftscore": null, "siftprediction": null, "polyphenscore": null, "polyphenprediction": null, "evidences": { "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14500344, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 21917714, 22113612, 22281684, 23263490, 23302800, 23685455, 24455489, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "cosmic_study": [] }, "xrefs": { "cosmicmutationid": [], "clinvaraccession": [] }, "variant_type": "Disease", "disease": "Astrocytoma, low-grade, somatic", "disease_symbol": null, "disease_alt_symbol": null, "bed_comments": null, "pub_med_references": [ 12068308, 12198537, 12447372, 12619120, 12644542, 12670889, 12794760, 12960123, 14500344, 14513361, 14602780, 15001635, 15126572, 15181070, 15342696, 15356022, 15386408, 15687339, 15998781, 16015629, 16174717, 16187918, 16772349, 17374713, 17488796, 17785355, 18398503, 19571295, 20818844, 20823850, 21107320, 21107323, 21917714, 22113612, 22281684, 23263490, 23302800, 23685455, 24455489, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ] } ] } ], "weill_cornell_medicine_pmkb": [ { "version": "03-Jul-2024", "items": [ { "tier": 1, "definition": [ "BRAF V600E", "BRAF codon(s) 600 any" ], "interpretations": "Eighty percent of all thyroid cancers are papillary thyroid carcinomas (PTCs). BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway and V600E is an activating mutation of BRAF. The BRAF V600E mutation has been reported in 45% of patients with papillary thyroid carcinoma. The BRAF V600E-like PTC's (BVL) and the RAS-like PTC (RL-PTC) are fundamentally different in their genomic, epigenomic, and proteomic profiles. Presence of a BRAF p.Val600Glu (V600E) mutation is highly specific for papillary thyroid carcinoma and is only rarely associated with the follicular variant PTC , other well-differentiated thyroid neoplasms or nodular goiters. The possible prognostic impact of BRAF V600E mutations in papillary carcinoma of the thyroid continues to be studied. \nFDA approved dabrafenib and trametinib administered together for the treatment of BRAF V600E mutation-positive anaplastic thyroid cancer. ", "tissues": [ "Thyroid" ], "tumour_types": [ "Papillary Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 12068308, 25417114, 26124474 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E", "BRAF codon(s) 600 any", "BRAF V600D", "BRAF V600K", "BRAF V600R", "BRAF V600M", "BRAF V600G" ], "interpretations": "Presence of a BRAF c.1799T>A, p.Val600Glu (V600E) mutation in a microsatellite unstable colorectal carcinoma indicates that the tumor is probably sporadic and not associated with Lynch syndrome (HNPCC). However, if a BRAF mutation is not detected, the tumor may either be sporadic or Lynch syndrome associated. Detection of BRAF mutations may also be useful in determining patient eligibility for anti-EGFR treatment. Approximately 8--15% of colorectal cancer (CRC) tumors harbor BRAF mutations. The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival. Some studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab in the chemotherapy-refractory setting. BRAF V600-mutated CRCs may not be sensitive to V600E targeted TKIs.\n\nDrug: Vemurafenib + Panitumumab,\nEncorafenib + Binimetinib + Cetuximab,\nRadiation + Trametinib + Fluorouracil", "tissues": [ "Colon", "Rectum" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": [ 12068308, 17195912, 19001320, 19571295, 19616446, 19884556, 22281684, 23438367 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E", "BRAF codon(s) 600 any", "BRAF V600D", "BRAF V600K", "BRAF V600R", "BRAF V600M", "BRAF V600G" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF mutations are present in approximately 50% to 60% of cutaneous melanomas and are also present at lower frequencies in other melanoma subtypes. The hotspot for mutations in BRAF is at codon Val600 and the most common one is p.Val600Glu (V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for melanoma therapy in certain settings.\nDrug: \nVemurafenib\nDabrafenib\nDabrafenib + Trametinib\nVemurafenib + Cobimetinib\nTrametinib", "tissues": [ "Skin" ], "tumour_types": [ "Melanoma" ], "disease_or_trait": null, "pub_med_references": [ 12068308, 22157295, 23415641, 23770823, 24331719 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E", "BRAF codon(s) 600 any" ], "interpretations": "BRAF alterations have been described in a wide spectrum of brain tumors, including in gliomas and glioneuronal tumors. BRAFV600E mutations have been found in approximately 10--15% of pilocytic astrocytoma and in approximately 5--10% of pediatric diffusely infiltrating gliomas, including diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III) and glioblastomas (WHO grade IV), but in less than 2% of comparable adult gliomas. This mutation is potentially targetable.", "tissues": [ "Spinal Cord", "Brain", "Supratentorial", "Infratentorial" ], "tumour_types": [ "Glioblastoma", "Pleomorphic Xanthoastrocytoma", "Ganglioglioma", "Neuroepithelial Neoplasm", "NOS", "Neuroepithelial neoplasm", "high grade", "Astrocytoma", "Pilocytic" ], "disease_or_trait": null, "pub_med_references": [ 21274720, 23547069, 24725538 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E", "BRAF codon(s) 600 any" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 40-70% of Langerhans cell histiocytosis and approximately 50% of Erdheim-Chester disease. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings, and clinical trials for advanced BRAF V600 mutation-positive tumors using targeted therapy (often in combination with other therapy) may be available (clinical trials.gov).\n", "tissues": [ "Bone", "Lung", "Bone Marrow", "Lymph Node", "Skin" ], "tumour_types": [ "Langerhans Cell Histiocytosis", "Histiocytic and Dendritic Cell Neoplasms" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E" ], "interpretations": "Mutations in beta catenin (CTNNB1) are seen in about 90% of adamantinomatous craniopharyngiomas and mutations in BRAF (V600E) in papillary craniopharyngiomas. Adamantinomatous and papillary craniopharyngiomas have been shown to carry clonal mutations that are typically mutually exclusive but may occasionally coexist. These findings indicate that the adamantinomatous and papillary subtypes have distinct molecular underpinnings, each principally driven by mutations in a single well-established oncogene - CTNNB1 in the adamantinomatous form and BRAF in the papillary form, independent of age. This may have implications for the diagnosis and treatment of these tumors. Treatment with the BRAF inhibitor vemurafenib has been reported to result in disease stabilization in a patient with a papillary craniopharyngioma with a BRAF V600E mutation.", "tissues": [ "Brain" ], "tumour_types": [ "Craniopharyngioma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600E" ], "interpretations": "BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway and V600E is an activating mutation of BRAF. The BRAF V600E mutation has been reported in 45% of patients with papillary thyroid carcinoma, which comprise 80 % of all thyroid cancers. Presence of a BRAF p.Val600Glu (V600E) mutation is highly specific for papillary thyroid carcinoma and is only rarely associated with the follicular variant PTC, other thyroid neoplasms, or nodular goiters. Anaplastic thyroid carcinomas are rare, highly aggressive, undifferentiated tumors that comprise 1% to 2% of all thyroid cancers in the United States. Well-differentiated papillary thyroid cancer, in which BRAF V600 mutations are an early and common driver mutation, precedes or coexists with approximately 50% of anaplastic thyroid carcinomas. Between 20% and 50% of anaplastic thyroid carcinomas harbor activating BRAF V600 mutations, with unknown prognostic significance. The possible prognostic impact of BRAF V600E mutations in carcinoma of the thyroid continues to be studied. ", "tissues": [ "Thyroid" ], "tumour_types": [ "Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 26878173 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600D", "BRAF codon(s) 600 any" ], "interpretations": "Drug\nVemurafenib\nDabrafenib\nDabrafenib + Trametinib\nVemurafenib + Cobimetinib", "tissues": null, "tumour_types": [ "Melanoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF codon(s) 600 any", "BRAF V600G" ], "interpretations": "Vemurafenib", "tissues": null, "tumour_types": [ "Langerhans Cell Histiocytosis" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF codon(s) 600 any", "BRAF V600M" ], "interpretations": "Vemurafenib\nDabrafenib\nDabrafenib + Trametinib\nVemurafenib + Cobimetinib\nVemurafenib + Panitumumab\nEncorafenib + Binimetinib + Cetuximab\nRadiation + Trametinib + Fluorouracil", "tissues": [ "Colon", "Lung" ], "tumour_types": [ "Melanoma", "Langerhans Cell Histiocytosis", "Non-Small Cell Lung Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 19884556, 23438367, 27080216 ], "variants": [ { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 1, "definition": [ "BRAF V600D", "BRAF V600E", "BRAF V600K", "BRAF V600R", "BRAF codon(s) 600 any" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 100% of Hairy cell leukemia, 40-70% of Langerhans cell histiocytosis, approximately 50% of Erdheim-Chester disease, approximately 5% of diffuse large B cell lymphoma and plasma cell neoplasms and less than 5% of chronic lymphocytic leukemia. Some types of Hairy Cell Leukemia (eg, Hairy Cell Leukemia-Variant, Hairy Cell Leukemia with IgHV4-34 rearrangement) are negative for BRAF V600E mutation and may have MAP2K1 mutations. While some reports have found that 10-20% of cases of acute leukemias (ALL or AML) may have BRAF mutations, other reports have described no BRAF in those diseases or in myeloid diseases such as MDS or CML. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). B-Raf inhibitors(eg, Vemurafenib) have been FDA approved for therapy for various tumor types and have been used in Hairy Cell Leukemia in some clinical settings, including in combination with other therapy.", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Hairy Cell Leukemia" ], "disease_or_trait": null, "pub_med_references": [ 22230299, 22639828, 23009221, 23088640, 24428489, 24495477, 26352686, 26941398 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600E" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in <2% of head and neck squamous cell carcinomas. The hotspot for mutations in BRAF is at codon Val600 and the most common one is p.Val600Glu (V600E). Various B-RAF inhibitors have been FDA approved for cancer therapy in certain settings. ", "tissues": [ "Larynx", "Oral Cavity" ], "tumour_types": [ "Squamous Cell Carcinoma" ], "disease_or_trait": null, "pub_med_references": [ 12068308 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600D", "BRAF V600E", "BRAF V600K", "BRAF V600R", "BRAF codon(s) 600 any", "BRAF any mutation" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. Mutations of B-RAF have been described in up to 100% of Hairy cell leukemia, 40-70% of Langerhans cell histiocytosis, approximately 50% of Erdheim-Chester disease, approximately 5% of diffuse large B cell lymphoma and plasma cell neoplasms and less than 5% of chronic lymphocytic leukemia. While some reports have found that 10-20% of cases of acute leukemias (ALL or AML) may have BRAF mutations, other reports have described no BRAF in those diseases or in myeloid diseases such as MDS or CML. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain clinical settings. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Leukemia of Unspecified Cell Type", "Acute Myeloid Leukemia", "Anemia", "Unspecified", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Chronic Neutrophilic Leukemia", "Cytopenia", "Eosinophilia", "Essential Thrombocythemia", "Leukocytosis", "Leukopenia", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Monocytosis", "Myelodysplastic Syndrome", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Other Acute Leukemia", "Polycythemia Vera", "Polycythemia", "Primary Myelofibrosis", "T Lymphoblastic Leukemia/Lymphoma", "Thrombocytopenia", "Thrombocytosis", "Chronic Lymphocytic Leukemia", "Diffuse Large B Cell Lymphoma" ], "disease_or_trait": null, "pub_med_references": [ 22230299, 22639828, 23009221, 23088640, 24428489, 24495477 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 }, { "aa_positions": [ 600 ], "coding_impact": "any", "definition": "BRAF codon(s) 600 any", "type": "codon", "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600E" ], "interpretations": "BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Activating BRAF(V600E) (Val600Glu) mutations have been identified in approximately 1-2% of lung adenocarcinomas. Various BRAF inhibitors (Vemurafenib, Dabrafenib, and Trametinib) have been FDA approved for therapy for some tumor types in certain clinical settings. Of note, Dabrafenib and Trametinib are approved for metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations.", "tissues": [ "Lung" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": [ 22663011, 27080216 ], "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600E" ], "interpretations": "B-RAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). Various B-Raf inhibitors(Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings, and clinical trials for advanced BRAF V600 mutation-positive tumors using targeted therapy (often in combination with other therapy) may be available (clinical trials.gov). It has been found that BRAF V600E has a mutation frequency of 2% in pancreatic cancer. A small study showed that no BRAF mutations were present in cases without KRAS mutations and in the few cases with BRAF mutations, a KRAS mutation was also present. ", "tissues": [ "Pancreas" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600E" ], "interpretations": "BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. The hotspot for mutations in BRAF is at codon Val600 and these are activating mutations. The most common activating mutation is p.Val600Glu(V600E). BRAF mutation frequencies are highly controversial in biliary tract cancers ranging from 0 to 33% for BRAF V600E. As most studies with high BRAF mutation rates were performed on European cohorts, this has raised the question of whether these discordant results represent a regional difference in the genetics of biliary tract cancer. In large cohort of biliary tract cancers including intrahepatic cholangiocarcinomas, extrahepatic cholangiocarcinomas, and adenocarcinomas of the gallbladder, BRAF V600E mutations were only rarely found in intrahepatic cholangiocarcinomas and were not identified in any cases of gallbladder adenocarcinoma. The clinicopathologic significance of BRAF V600E remains to be further elucidated in adenocarcinoma of the gallbladder. Various BRAF inhibitors (Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings. These results should be interpreted in the clinical and radiographic context. ", "tissues": [ "Gall Bladder" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] }, { "tier": 2, "definition": [ "BRAF V600E" ], "interpretations": "BRAF is a member of the RAF-family of kinases which plays an important role in the RAS-RAF-MEK-ERK mitotic signaling pathway. BRAF V600E lies within the activation segment of the kinase domain of the BRAF protein and confers a gain of function. BRAF mutations are infrequent in urothelial carcinoma and are identified in 3-5% of cases. Various BRAF inhibitors (Vemurafenib, Dabrafenib) have been FDA approved for therapy for some tumor types in certain settings. The use of BRAF inhibitors in a number of other cancer types harboring BRAF V600E mutations are under investigation (clinicaltrials.gov). The clinicopathologic effects of BRAF in urothelial carcinoma remains to be fully elucidated.", "tissues": [ "Kidney", "Bladder", "Ureter" ], "tumour_types": [ "Urothelial Carcinoma" ], "disease_or_trait": null, "pub_med_references": null, "variants": [ { "coding_impact": "any", "definition": "BRAF V600E", "type": "variantId", "variants": [ "10190071404531360004", "10380071407533360004" ], "gene_id": 2273 } ] } ] } ], "wustl_civic": [ { "version": "08-Dec-2023", "items": [ { "asco_entry": null, "clinical_significance": "Positive", "disease": "Thyroid Cancer", "doid": "1781", "drug_interaction_type": null, "drugs": null, "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/79", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "BRAF V600E is shown to be associated with the tall-cell variant of papillary thyroid cancer.", "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": [ 21594703 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "variant_origin": "Somatic", "variant_summary": null, "assertion_details": [ { "amp_category": "Tier I - Level A", "assertion_civic_url": "https://civicdb.org/links/assertions/7", "assertion_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.", "assertion_direction": "Supports", "assertion_id": "7", "assertion_summary": "BRAF V600E mutant melanoma is sensitive to dabrafenib and trametinib combination therapy", "assertion_type": "Predictive", "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drugs": [ "Dabrafenib", "Trametinib" ], "evidence_item_ids": [ "6938", "6178", "3758", "6940" ], "fda_companion_test": true, "gene": "BRAF", "nccn_guideline": "Melanoma", "nccn_guideline_version": "2.2018", "normalized_drug": [ "Dabrafenib, Trametinib" ], "regulatory_approval": true }, { "amp_category": "Tier I - Level A", "assertion_civic_url": "https://civicdb.org/links/assertions/10", "assertion_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).", "assertion_direction": "Supports", "assertion_id": "10", "assertion_summary": "BRAF V600E mutant melanoma is sensitive to vemurafenib and cobimetinib combination therapy", "assertion_type": "Predictive", "clinical_significance": "Sensitivity/Response", "disease": "Melanoma", "doid": "1909", "drugs": [ "Cobimetinib", "Vemurafenib" ], "evidence_item_ids": [ "6044", "1421", "6966" ], "fda_companion_test": true, "gene": "BRAF", "nccn_guideline": "Melanoma", "nccn_guideline_version": "2.2018", "normalized_drug": [ "Cobimetinib, Vemurafenib" ], "regulatory_approval": true }, { "amp_category": "Tier I - Level A", "assertion_civic_url": "https://civicdb.org/links/assertions/20", "assertion_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.", "assertion_direction": "Supports", "assertion_id": "20", "assertion_summary": "BRAF V600E indicates poor prognosis in advanced colorectal cancer", "assertion_type": "Prognostic", "clinical_significance": "Poor Outcome", "disease": "Colorectal Cancer", "doid": "9256", "drugs": null, "evidence_item_ids": [ "7157", "7156", "1552", "103", "7159", "7158" ], "fda_companion_test": false, "gene": "BRAF", "nccn_guideline": "Colon Cancer", "nccn_guideline_version": "2.2017", "normalized_drug": null, "regulatory_approval": null } ], "civic_variant_evidence_score": "CA123643", "variant_groups": null, "molecular_profile_civic_url": "https://civicdb.org/links/molecular_profiles/12", "molecular_profiles": [ { "molecular_profile": { "evidence_item_ids": [ 6262 ], "name": "BRAF Amplification AND ( BRAF V600E OR BRAF V600K )", "summary": null, "variant": [ { "gene": "BRAF", "hgvs": "V600E", "variant_ids": [ 10190071404531360004 ] }, { "gene": "BRAF", "hgvs": "V600K", "variant_ids": [ 10190071404531360006 ] } ] }, "molecular_profile_civic_id": 4174 } ] }, { "asco_entry": null, "clinical_significance": "Positive", "disease": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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/82", "evidence_direction": "Does Not Support", "evidence_level": "B", "evidence_statement": "BRAF status does not predict outcome in patients treated with dacarbazine or temozolomide.", "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": [ 24586605 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Trametinib", "Mirdametinib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/86", "evidence_direction": "Does Not Support", "evidence_level": "D", "evidence_statement": "In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP but does not show resistance to MEK inhibitors.", "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": [ "Trametinib" ], "phenotypes": null, "pub_med_references": [ 24576830 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Sorafenib", "Panitumumab" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/89", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Cetuximab or panitumumab may be ineffective in patients with BRAF mutation unless BRAF inhibitor such as Sorafenib is introduced.", "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", "Sorafenib" ], "phenotypes": null, "pub_med_references": [ 19001320 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Vemurafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/90", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "In the setting of BRAF(V600E), NF1 loss resulted in elevated activation of RAS-GTP and resistance to RAF inhibitors.", "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": [ 24576830 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/95", "evidence_direction": "Supports", "evidence_level": "B", "evidence_statement": "Dabrafenib with trametinib provides higher response rate and lower toxicity (as compared to chemotherapy) in patients with 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": null, "normalized_drug": [ "Dabrafenib, Trametinib" ], "phenotypes": null, "pub_med_references": [ 24583796 ], "rating": "5", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "PLX4720", "Pictilisib Bismesylate" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/96", "evidence_direction": "Supports", "evidence_level": "D", "evidence_statement": "Combined PI3K inhibitor GDC0941 and BRAF inhibitor PLX4720 administration to NSG mice subcutanousely injected with colorectal cell lines with a BRAF V600E mutation effectively inhibited tumor growth and reduced cellular proliferation.", "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": [ "Pictilisib" ], "phenotypes": null, "pub_med_references": [ 23845441 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "PLX4720", "Nutlin-3" ], "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 colorectal 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": "2023-01-09 21:46:25 UTC", "nct_ids": null, "normalized_drug": null, "phenotypes": null, "pub_med_references": [ 23812671 ], "rating": "2", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Bevacizumab", "Capecitabine", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Dabrafenib" ], "entrez_id": null, "evidence_civic_url": "https://civicdb.org/links/evidence_items/1406", "evidence_direction": "Does Not Support", "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": "2023-01-09 21:46:24 UTC", "nct_ids": [ "NCT00880321" ], "normalized_drug": [ "Dabrafenib" ], "phenotypes": null, "pub_med_references": [ 22608338 ], "rating": "3", "representative_transcript": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Cetuximab", "Gefitinib", "Vemurafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "drugs": [ "Vemurafenib", "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Panitumumab", "Vemurafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Irinotecan", "Vemurafenib", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "Panitumumab" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Bevacizumab", "Capecitabine", "Oxaliplatin" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "FOLFOX-4 Regimen" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "drugs": [ "Trametinib", "Dabrafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "drugs": [ "Trametinib", "Dabrafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Anaplastic Carcinoma", "doid": "0080522", "drug_interaction_type": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Anaplastic 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Panitumumab", "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "Dabrafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "Dabrafenib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Anaplastic Carcinoma", "doid": "0080522", "drug_interaction_type": null, "drugs": [ "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "drugs": [ "Dabrafenib", "Trametinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Encorafenib", "Cetuximab", "Binimetinib" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "Cetuximab", "Irinotecan" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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", "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "Thyroid Gland Papillary 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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": [ "Encorafenib", "Cetuximab" ], "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": null, "transcripts": null, "variant": "V600E", "variant_civic_url": null, "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": "14-Sep-2024", "items": [ { "annotations": { "NCBI 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"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, 23263490, 22281684 ], "pub_med_references": [ 22281684, 23263490, 23302800, 23685455, 24455489, 24512911, 24670642, 24717435, 25079330, 28854169, 29925953 ], "disease_name": [ "Astrocytoma, low-grade, somatic", "Carcinoma of colon", "Cardio-facio-cutaneous syndrome", "Cerebral arteriovenous malformation", "Colonic neoplasm" ], "annotation_id": "VAR_018629" } ] } } ] } ], "acmg_annotation": { "version_name": "12.1.1", "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": 5.271, "pathogenic_score": 21, "pathogenic_subscore": "Pathogenic", "total_score": 21, "verdict": "Pathogenic" }, "classifications": [ "PS3_Very Strong", "PM1_Strong", "PM5_Strong", "PP3_Moderate", "PP5_Moderate", "PM2_Supporting" ] }, "classifications": [ { "name": "PS3", "met_criteria": true, "user_explain": [ "Combined evidence strength is Very Strong (score = 10).", "Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Jul '24, 37 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:26678033%% 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%%." ], "strength": "Very Strong" }, { "name": "PM1", "met_criteria": true, "user_explain": [ "Hot-spot of length 17 amino-acids has 58 missense/in-frame variants (51 pathogenic variants, 7 uncertain variants and no benign), which qualifies as strong pathogenic.", "UniProt protein BRAF_HUMAN domain 'Protein kinase' has 291 missense/in-frame variants (152 pathogenic variants, 138 uncertain variants and 1 benign variant), which qualifies as moderate pathogenic." ], "strength": "Strong" }, { "name": "PM5", "met_criteria": true, "user_explain": [ "Alternative variant ##chr7:140453137 C⇒T## (Val600Met) is classified Pathogenic by the VarSome community in article %%PUBMED:29168975%% (confirmed using the germline classifier).", "Alternative variant ##chr7:140453137 C⇒G## (Val600Leu) is classified Likely Pathogenic by the VarSome community (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⇒G## (Val600Ala) is classified Likely Pathogenic, 0 stars, by ClinVar (confirmed using the germline classifier).", "Alternative variant ##chr7:140453136 A⇒C## (Val600Gly) is classified Pathogenic by the VarSome community in article %%PUBMED:23110010%% (confirmed using the germline classifier).", "Alternative variant ##chr7:140453136 AC⇒TT## (Val600Lys) is classified Pathogenic by the VarSome community in article %%PUBMED:29483135%% (confirmed using the germline classifier).", "Alternative variant ##chr7:140453136 AC⇒CT## (Val600Arg) is classified Pathogenic by the VarSome community (confirmed using the germline classifier).", "Alternative variant ##chr7:140453136 AC⇒CG## (Val600Arg) is classified Pathogenic by the VarSome community in article %%PUBMED:25763513%% (confirmed using the germline classifier).", "Alternative variant ##chr7:140453135 CA⇒AT## (Val600Asp) is classified Pathogenic by the VarSome community in article %%PUBMED:22508706%% (confirmed using the germline classifier).", "9 pathogenic alternative variants identified." ], "strength": "Strong" }, { "name": "PP3", "met_criteria": true, "user_explain": [ "MetaRNN = 0.883 is between 0.841 and 0.939 ⇒ moderate pathogenic." ], "strength": "Moderate" }, { "name": "PP5", "met_criteria": true, "user_explain": [ "Combined evidence strength is Moderate (score = 2).", "Moderate: the VarSome community has classified this variant as Pathogenic, citing 64 articles (%%PUBMED:33188936%%, %%PUBMED:32305313%%, %%PUBMED:32291725%%, %%PUBMED:31602213%%, %%PUBMED:30892822%% and 59 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 Cardio-Facio-Cutaneous Syndrome 1, Omim:115150, Cardiofaciocutaneous Syndrome, Cardiofaciocutaneous Syndrome 1, Cardiofaciocutaneous Syndrome 115150 and 36 more, according to CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype.", "mode_of_inheritance": "AD, based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype." } }, "amp_annotation": { "version_name": "12.1.1", "verdict": { "tier": "Tier I", "approx_score": 3.345 }, "classifications": [ { "name": "Crtd", "tier": "Tier I", "user_explain": { "Tier I": [ "DoCM reports 6 entries classified Tier I citing 78 articles (%%PUBMED:26678033%%, %%PUBMED:26619011%%, %%PUBMED:25989278%%, %%PUBMED:25370471%%, %%PUBMED:25157968%% and 73 more) related to the following 6 cancers: Bowel, Gastrointestinal Stromal Tumor, Lung, Melanoma, Ovary/Fallopian Tube and Thyroid.", "CIViC reports 11 entries, 11 x 5-star rated , listing 6 drugs: \"Binimetinib\", \"Cetuximab\", \"Cetuximab, Encorafenib\", \"Dabrafenib, Trametinib\", \"Encorafenib\" and \"Vemurafenib\" related to the following 4 cancers: Bowel, Melanoma, Skin and Thyroid.", "PMKB rates this variant Tier I citing 27 articles (%%PUBMED:27080216%%, %%PUBMED:26941398%%, %%PUBMED:26878173%%, %%PUBMED:26352686%%, %%PUBMED:26124474%% and 22 more) related to the following 14 cancers: Adenocarcinoma, NOS, Astrocytoma, Craniopharyngioma, Epithelial Neoplasm, Ganglioglioma and 9 more." ], "Tier II": [ "ClinVar classifies this variant as Pathogenic, rated 2 stars related to the following 30 cancers: Astrocytoma, low-grade, somatic, Bowel, CNS/Brain, Cancer, Colorectal Neoplasms and 25 more, with 32 somatic submissions, citing 111 articles (%%PUBMED:34476331%%, %%PUBMED:31891627%%, %%PUBMED:29925953%%, %%PUBMED:28854169%%, %%PUBMED:26678033%% and 106 more).", "DoCM reports 19 entries classified Tier II citing 83 articles (%%PUBMED:26678033%%, %%PUBMED:26619011%%, %%PUBMED:25989278%%, %%PUBMED:25370471%%, %%PUBMED:25157968%% and 78 more) related to the following 15 cancers: Bowel, CNS/Brain, Gastrointestinal Stromal Tumor, Glioblastoma Multiforme and 10 more.", "CIViC reports 70 entries, 46 x 3-star and 24 x 4-star rated , listing 23 drugs: \"Bevacizumab\", \"Bevacizumab, Capecitabine, Oxaliplatin\", \"Binimetinib\", \"Capecitabine\", \"Cetuximab\" and 18 more related to the following 19 cancers: Biliary Tract, Bowel, Cancer, Childhood Low-Grade Glioma, Childhood Pilocytic Astrocytoma and 14 more.", "PMKB rates this variant Tier II citing 9 articles (%%PUBMED:27080216%%, %%PUBMED:24495477%%, %%PUBMED:24428489%%, %%PUBMED:23088640%%, %%PUBMED:23009221%% and 4 more) related to the following 22 cancers: Acute Leukemia Of Unspecified Cell Type, Acute Myeloid Leukemia, Adenocarcinoma, NOS, B-Lymphoblastic Leukemia/Lymphoma, Bladder/Urinary Tract and 17 more." ] }, "approx_score": 3.2 }, { "name": "Drug", "tier": "Tier I", "user_explain": { "Tier I": [ "5 drugs (curated), reported by CIViC and PMKB, for 6 cancers - but no patient cancer type was provided for matching.", "Binimetinib, Cetuximab, Fluorouracil and Panitumumab (curated), reported by PMKB, for 4 cancers (Adenocarcinoma, NOS, Langerhans Cell Histiocytosis, Melanoma and Non-Small Cell Lung Cancer) - but no patient cancer type was provided for matching.", "Dabrafenib, Trametinib and Vemurafenib (curated), reported by PMKB, for 2 cancers (Adenocarcinoma, NOS and Papillary Carcinoma) - but no patient cancer type was provided for matching.", "Beta and Braf Inhibitor (curated), reported by PMKB, related to Craniopharyngioma - but no patient cancer type was provided for matching.", "Cobimetinib, Vemurafenib (curated), reported by CIViC, related to Melanoma - but no patient cancer type was provided for matching." ], "Tier II": [ "15 drugs (curated), reported by CIViC and PMKB, for 24 cancers - but no patient cancer type was provided for matching.", "5 drugs (curated), reported by CIViC, for 9 cancers - but no patient cancer type was provided for matching." ] }, "approx_score": 5.0 }, { "name": "Germ", "tier": "Tier I", "user_explain": { "Tier I": [ "This variant is classified Pathogenic, by the germline classifier rules PS3_Very Strong, PM1_Strong, PM5_Strong, PP3_Moderate, PP5_Moderate and PM2_Supporting." ] }, "approx_score": 3.1 }, { "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." ] }, "total_samples": 4904, "approx_score": 2.0 }, { "name": "Pubs", "tier": "Tier I", "user_explain": { "Tier I": [ "VarSome users have linked 73 articles stating the variant is pathogenic (%%PUBMED:38269481%%, %%PUBMED:37296851%%, %%PUBMED:37231247%%, %%PUBMED:36579983%%, %%PUBMED:33188936%% and 68 more)(7 entries have been automatically lifted over from hg38)." ] }, "approx_score": 3.0 }, { "name": "Path", "tier": "Tier II", "user_explain": { "Tier II": [ "Consensus associates gene BRAF with the following 21 cancers: Acute Myeloid Leukemia, Bladder/Urinary Tract, Breast, Chromosomal and microsatellite instability in colorectal cancer, Colorectal cancer and 16 more.", "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.", "KEGG reports that gene BRAF is involved in ErbB signaling pathway, Insulin signaling pathway, MAPK signaling pathway and mTOR signaling pathway. Also, associates BRAF with the following 12 cancers: Acute Myeloid Leukemia, Bladder/Urinary Tract, Colorectal cancer, Endometrial cancer, Glioma and 7 more.", "Mondo associates gene BRAF with the following 9 cancers: Colorectal Cancer, Craniopharyngioma, Differentiated Thyroid Carcinoma, Hairy Cell Leukemia, Langerhans Cell Histiocytosis and 4 more.", "The Human Protein Atlas classifies BRAF as an oncogene." ] }, "approx_score": 4.0 }, { "name": "Type", "tier": "Tier III", "user_explain": { "Tier III": [ "ACMG rule PVS1 did not trigger.", "ACMG rule PM4 did not trigger.", "Variant is not predicted splicing: no prediction from MaxEntScan." ] }, "approx_score": 2.0 }, { "name": "Freq", "tier": "Tier II", "user_explain": { "Tier II": [ "ACMG rule PM2 was triggered with strength Supporting: 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": 2.0 }, { "name": "Pred", "tier": "Tier III", "user_explain": { "Tier III": [ "Uncertain Significance computational verdict based on 1 pathogenic prediction from MetaRNN, conflicting with no benign predictions (and 1 uncertain prediction from DANN)." ] }, "approx_score": 1.0 } ], "sample_findings": { "sex": "53.3% 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": "ENSP00000288602", "ccds": "CCDS5863.1", "cdsposition": "1799/2301", "cdnaposition": "1860/2480", "biotype": "Protein_Coding", 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