Available parameters and response documentation is available here

GET /lookup/BRAF:V600E?add-source-databases=ncbi-clinvar2,cancer-hotspots
HTTP 200 OK
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Content-Type: application/json ;utf-8
ETag: "8cf1939b3538ef8a476cc2d86da0ae938b2d0b9867ee9eee6e502881a26baee4"
Vary: Accept

{
  "chromosome": "chr7",
  "alt": "T",
  "ref": "A",
  "pos": 140453136,
  "variant_id": "10190071404531360004",
  "variant_type": "SNV",
  "cytobands": "7q34",
  "ncbi_clinvar2": [
    {
      "version": "01-Apr-2024",
      "review_status": "criteria provided, multiple submitters, no conflicts",
      "review_stars": 2,
      "variation_id": 13961,
      "num_submitters": 15,
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      "clinical_significance": [
        "Pathogenic"
      ],
      "last_evaluation": "20240305",
      "origin": null,
      "accessions": [
        {
          "accession_id": "RCV003458334",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "criteria provided, single submitter",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Vascular malformation",
          "date_created": 20231224,
          "diseases": [
            {
              "normalized_disease": [
                "Vascular Malformation"
              ],
              "symbols": {
                "medgen": "C0158570",
                "mondo": "MONDO:0024291"
              },
              "names": [
                "Vascular Malformation"
              ]
            }
          ],
          "review_stars": 1,
          "review_date": 20231022,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [
                "The BRAF c.1799T>A (p.Val600Glu) variant was identified at an allelic fraction consistent with somatic origin. This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs in a highly conserved residue within the CR3 activation segment, amino acids 594-627, of BRAF that is defined as a critical functional domain (Wellbrock C, et al., PMID: 15520807; Gelb BD, et al., PMID: 29493581). The BRAF c.1799T>A (p.Val600Glu) variant in a somatic state has been reported in multiple individuals affected with sporadic vascular malformations, brain arteriovenous malformation (BAVM) and spinal arteriovenous malformation (SAVM) (Hong T, et al., PMID: 30544177; Al-Olabi L, et al., PMID: 29461977; Goss JA, et al., PMID: 31891627; Li H, et al., PMID: 34530633). The BRAF c.1799T>A (p.Val600Glu) variant has been reported in the ClinVar database as pathogenic by numerous submitters (ClinVar ID: 13961). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies show constitutively active kinase activity (Rodriguez-Viciana P, et al., PMID: 16439621; Sarkozy A, et al., PMID:19206169; Al-Olabi L, et al., PMID: 29461977). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as pathogenic."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "Clinical Genomics Laboratory, Washington University in St. Louis",
              "review_date": 20231022,
              "origin": "somatic",
              "method": "clinical testing",
              "submitter_date": 20231212,
              "diseases": [
                {
                  "normalized_disease": [
                    "Vascular Malformation"
                  ],
                  "names": [
                    "Vascular Malformation"
                  ]
                }
              ],
              "date_updated": 20231224,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "criteria provided, single submitter",
              "accession_id": "SCV004176942"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV002051586",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lymphangioma",
          "date_created": 20220328,
          "diseases": [
            {
              "normalized_disease": [
                "Lymphangioma"
              ],
              "symbols": {
                "medgen": "C0024221",
                "mondo": "MONDO:0002013",
                "human_phenotype_ontology": "HP:0100764"
              },
              "names": [
                "Lymphangioma"
              ]
            }
          ],
          "review_stars": 0,
          "review_date": 20220209,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [
                "The Val600Glu variant in BRAF was observed at very low levels (VAF 0.3-2%) in lymphatic malformation tissue from three unrelated individuals using high depth NGS (VANseq), confirmatory digital droplet PCR, and BRAF V600E immunohistochemistry."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "James Bennett Lab, Seattle Childrens Research Institute",
              "review_date": 20220209,
              "origin": "somatic",
              "method": "research",
              "submitter_date": 20220325,
              "diseases": [
                {
                  "symbols": {
                    "hp": "HP:0100764"
                  }
                }
              ],
              "date_updated": 20220328,
              "finding": [
                {
                  "symbols": {
                    "hp": "HP:0100766"
                  },
                  "normalized_phenotype": [
                    "Abnormal Lymphatic Vessel Morphology"
                  ]
                }
              ],
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV002318371"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000430562",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Multiple myeloma",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20190831,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center",
              "review_date": 20190831,
              "origin": "somatic",
              "method": "clinical testing",
              "submitter_date": 20190912,
              "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"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV001132084"
            },
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D009101"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504261"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV001248834",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nephroblastoma",
          "date_created": 20200719,
          "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_stars": 0,
          "review_date": 20190215,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Pediatric Oncology, Johns Hopkins University",
              "review_date": 20190215,
              "origin": "somatic",
              "method": "clinical testing",
              "submitter_date": 20200116,
              "diseases": [
                {
                  "normalized_disease": [
                    "Kidney Wilms Tumor"
                  ],
                  "normalized_cancer": [
                    "Wilms' Tumor"
                  ],
                  "names": [
                    "Kidney Wilms Tumor"
                  ]
                }
              ],
              "date_updated": 20200719,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV001147031"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000443745",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm of the large intestine",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20160531,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D015179"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504251"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000440802",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Papillary renal cell carcinoma, sporadic",
          "date_created": 20170308,
          "diseases": [
            {
              "normalized_disease": [
                "Papillary Renal Cell Carcinoma"
              ],
              "normalized_cancer": [
                "Papillary Renal Cell Carcinoma"
              ],
              "symbols": {
                "medgen": "C1336078",
                "mesh": "C538614"
              },
              "names": [
                "Papillary Renal Cell Carcinoma"
              ]
            }
          ],
          "review_stars": 0,
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          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "C538614"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504262"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000435441",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm of brain",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20160531,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D001932"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504256"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000417746",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Malignant melanoma of skin",
          "date_created": 20170308,
          "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_stars": 0,
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          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "C562393"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504257"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000429915",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lung adenocarcinoma",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20160531,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "C538231"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504264"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000424470",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Squamous cell carcinoma of the head and neck",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20160531,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "C535575"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504258"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000425166",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "finding": [
            {
              "normalized_phenotype": [
                "Brainstem Glioma"
              ],
              "symbols": {
                "medgen": "C0677865",
                "mondo": "MONDO:0002911",
                "human_phenotype_ontology": "HP:0010796"
              },
              "names": [
                "Childhood Brain Stem Glioma"
              ]
            }
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Brainstem glioma",
          "date_created": 20170308,
          "review_date": 20160531,
          "review_stars": 0,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submitter_date": 20160718,
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "date_updated": 20170308,
              "finding": [
                {
                  "symbols": {
                    "medgen": "C0677865"
                  }
                }
              ],
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504255"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000425847",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Glioblastoma",
          "date_created": 20170308,
          "diseases": [
            {
              "normalized_disease": [
                "Glioblastoma"
              ],
              "symbols": {
                "medgen": "C0017636",
                "mesh": "D005909",
                "mondo": "MONDO:0018177"
              },
              "names": [
                "Glioblastoma",
                "Giant Cell Glioblastoma (Histologic Variant)",
                "Gliosarcoma (Histologic Variant)"
              ]
            }
          ],
          "review_stars": 0,
          "review_date": 20160531,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160531,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D005909"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504252"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000443448",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20160513,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160513,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D009369"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504254"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "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
          ],
          "variant_id": 10190071404531360004,
          "accession_id": "RCV000067669",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Melanoma",
          "date_created": 20131031,
          "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_stars": 0,
          "review_date": 20160310,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160310,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D008545"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504249"
            },
            {
              "submission_description": [
                "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.",
                "Malignant Melanoma",
                "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.",
                "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.",
                "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.",
                "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.",
                "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.",
                "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.",
                "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.",
                "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.",
                "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.",
                "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.",
                "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.",
                "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.",
                "Colorectal Carcinoma",
                "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.",
                "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.",
                "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.",
                "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.",
                "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.",
                "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).",
                "Papillary Thyroid Carcinoma",
                "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.",
                "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.",
                "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.",
                "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.",
                "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.",
                "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.",
                "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.",
                "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.",
                "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.",
                "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.",
                "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.",
                "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.",
                "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.",
                "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.",
                "Nonseminomatous Germ Cell Tumors",
                "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.",
                "Astrocytoma",
                "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.",
                "Role in Neurodegeneration",
                "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.",
                "Variant Function",
                "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.",
                "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "OMIM",
              "review_date": 20140904,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220317,
              "diseases": [
                {
                  "normalized_disease": [
                    "Melanoma, Cutaneous Malignant, Susceptibility to, 1"
                  ],
                  "normalized_cancer": [
                    "MELANOMA, MALIGNANT, SOMATIC"
                  ],
                  "names": [
                    "Melanoma, Cutaneous Malignant, Susceptibility to, 1"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "pub_med_references": [
                12068308,
                12198537,
                12447372,
                12619120,
                12644542,
                12670889,
                12794760,
                12960123,
                14513361,
                14602780,
                15001635,
                15126572,
                15181070,
                15342696,
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                15687339,
                15998781,
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                17785355,
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                19571295,
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                20823850,
                21107320,
                21107323,
                22113612,
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                23302800,
                23685455,
                24512911,
                24670642,
                24717435,
                25079330,
                28854169,
                29925953
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000035247"
            }
          ]
        },
        {
          "accession_id": "RCV000420614",
          "allele_id": 29000,
          "review_description": "Likely pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Likely pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Colonic neoplasm",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20150714,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Likely pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20150714,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D003110"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Likely pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504260"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000662278",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Cystic epithelial invagination containing papillae lined by columnar epithelium",
          "date_created": 20180714,
          "diseases": [
            {
              "names": [
                "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium"
              ]
            }
          ],
          "review_stars": 0,
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          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Yale Center for Mendelian Genomics, Yale University",
              "review_date": 20150507,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20171127,
              "diseases": [
                {
                  "names": [
                    "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium"
                  ]
                }
              ],
              "date_updated": 20180714,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000784606"
            },
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Yale Center for Mendelian Genomics, Yale University",
              "review_date": 20150507,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220321,
              "diseases": [
                {
                  "names": [
                    "Cystic Epithelial Invagination Containing Papillae Lined By Columnar Epithelium"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV002106413"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000432628",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Neoplasm of ovary",
          "date_created": 20170308,
          "diseases": [
            {
              "normalized_disease": [
                "Ovarian Neoplasm",
                "Ovarian Cancer"
              ],
              "normalized_cancer": [
                "Ovary/Fallopian Tube",
                "Ovarian Cancer, Other"
              ],
              "symbols": {
                "omim": "167000",
                "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 Cancer",
                "Ovarian Neoplasm",
                "Ovarian Neoplasms"
              ]
            }
          ],
          "review_stars": 0,
          "review_date": 20141002,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20141002,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D010051"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504253"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000433305",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Lung carcinoma",
          "date_created": 20170308,
          "diseases": [
            {
              "normalized_disease": [
                "Lung Carcinoma"
              ],
              "normalized_cancer": [
                "Lung"
              ],
              "symbols": {
                "medgen": "C0684249",
                "mondo": "MONDO:0005138"
              },
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                25311215,
                24627688,
                23667368,
                29355391,
                29398453,
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              ],
              "names": [
                "Lung Carcinoma"
              ],
              "keyword": "Hereditary cancer syndrome"
            }
          ],
          "review_stars": 0,
          "review_date": 20141002,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20141002,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "omim": "211980"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504250"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000440540",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Gastrointestinal stromal tumor",
          "date_created": 20170308,
          "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_stars": 0,
          "review_date": 20141002,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20141002,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "D046152"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000504248"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "pub_med_references": [
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          "variant_id": 10190071404531360004,
          "accession_id": "RCV000014994",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Astrocytoma, low-grade, somatic",
          "date_created": 20130404,
          "diseases": [
            {
              "normalized_cancer": [
                "Astrocytoma, low-grade, somatic"
              ],
              "symbols": {
                "medgen": "C2674727"
              },
              "names": [
                "Astrocytoma, Low-Grade, Somatic"
              ]
            }
          ],
          "review_stars": 0,
          "review_date": 20140904,
          "variation_id": 13961,
          "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": [
            {
              "submission_description": [
                "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.",
                "Malignant Melanoma",
                "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.",
                "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.",
                "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.",
                "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.",
                "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.",
                "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.",
                "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.",
                "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.",
                "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.",
                "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.",
                "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.",
                "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.",
                "Colorectal Carcinoma",
                "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.",
                "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.",
                "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.",
                "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.",
                "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.",
                "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).",
                "Papillary Thyroid Carcinoma",
                "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.",
                "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.",
                "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.",
                "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.",
                "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.",
                "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.",
                "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.",
                "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.",
                "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.",
                "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.",
                "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.",
                "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.",
                "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.",
                "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.",
                "Nonseminomatous Germ Cell Tumors",
                "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.",
                "Astrocytoma",
                "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.",
                "Role in Neurodegeneration",
                "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.",
                "Variant Function",
                "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.",
                "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "OMIM",
              "review_date": 20140904,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220317,
              "diseases": [
                {
                  "normalized_cancer": [
                    "ASTROCYTOMA, LOW-GRADE, SOMATIC"
                  ],
                  "names": [
                    "Astrocytoma, Low-Grade, Somatic"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "pub_med_references": [
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              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000035250"
            }
          ]
        },
        {
          "pub_med_references": [
            12068308,
            12198537,
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          "variant_id": 10190071404531360004,
          "accession_id": "RCV000022677",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Nongerminomatous germ cell tumor",
          "date_created": 20130404,
          "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_stars": 0,
          "review_date": 20140904,
          "variation_id": 13961,
          "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": [
            {
              "submission_description": [
                "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.",
                "Malignant Melanoma",
                "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.",
                "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.",
                "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.",
                "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.",
                "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.",
                "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.",
                "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.",
                "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.",
                "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.",
                "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.",
                "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.",
                "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.",
                "Colorectal Carcinoma",
                "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.",
                "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.",
                "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.",
                "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.",
                "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.",
                "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).",
                "Papillary Thyroid Carcinoma",
                "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.",
                "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.",
                "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.",
                "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.",
                "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.",
                "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.",
                "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.",
                "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.",
                "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.",
                "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.",
                "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.",
                "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.",
                "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.",
                "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.",
                "Nonseminomatous Germ Cell Tumors",
                "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.",
                "Astrocytoma",
                "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.",
                "Role in Neurodegeneration",
                "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.",
                "Variant Function",
                "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.",
                "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "OMIM",
              "review_date": 20140904,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220317,
              "diseases": [
                {
                  "normalized_cancer": [
                    "NONSEMINOMATOUS GERM CELL TUMORS, SOMATIC"
                  ],
                  "names": [
                    "Nonseminomatous Germ Cell Tumors, Somatic"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "pub_med_references": [
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                12447372,
                12619120,
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                23685455,
                24512911,
                24670642,
                24717435,
                25079330,
                28854169,
                29925953
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000043966"
            }
          ]
        },
        {
          "pub_med_references": [
            12068308,
            12198537,
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            20823850,
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          ],
          "variant_id": 10190071404531360004,
          "accession_id": "RCV000014993",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Papillary thyroid carcinoma",
          "date_created": 20130404,
          "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_stars": 0,
          "review_date": 20140904,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "not provided",
              "submitter_name": "Database of Curated Mutations (DoCM)",
              "review_date": 20160310,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20160718,
              "diseases": [
                {
                  "symbols": {
                    "mesh": "C536915"
                  }
                }
              ],
              "date_updated": 20170308,
              "clinical_significance": [
                "not provided"
              ],
              "review_status": "no assertion provided",
              "accession_id": "SCV000504263"
            },
            {
              "submission_description": [
                "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.",
                "Malignant Melanoma",
                "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.",
                "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.",
                "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.",
                "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.",
                "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.",
                "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.",
                "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.",
                "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.",
                "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.",
                "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.",
                "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.",
                "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.",
                "Colorectal Carcinoma",
                "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.",
                "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.",
                "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.",
                "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.",
                "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.",
                "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).",
                "Papillary Thyroid Carcinoma",
                "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.",
                "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.",
                "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.",
                "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.",
                "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.",
                "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.",
                "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.",
                "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.",
                "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.",
                "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.",
                "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.",
                "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.",
                "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.",
                "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.",
                "Nonseminomatous Germ Cell Tumors",
                "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.",
                "Astrocytoma",
                "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.",
                "Role in Neurodegeneration",
                "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.",
                "Variant Function",
                "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.",
                "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "OMIM",
              "review_date": 20140904,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220317,
              "diseases": [
                {
                  "normalized_cancer": [
                    "Papillary Thyroid Cancer"
                  ],
                  "names": [
                    "Thyroid Carcinoma, Papillary, Somatic"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "pub_med_references": [
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                12447372,
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                23685455,
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                25079330,
                28854169,
                29925953
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              "review_status": "no assertion criteria provided",
              "accession_id": "SCV000035249"
            }
          ]
        },
        {
          "pub_med_references": [
            12068308,
            12198537,
            12447372,
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          ],
          "variant_id": 10190071404531360004,
          "accession_id": "RCV000014992",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Carcinoma of colon",
          "date_created": 20130404,
          "diseases": [
            {
              "normalized_disease": [
                "Colon Carcinoma",
                "Malignant Colon Neoplasm"
              ],
              "normalized_cancer": [
                "Bowel"
              ],
              "symbols": {
                "medgen": "C0699790",
                "mondo": "MONDO:0002032"
              },
              "pub_med": [
                19042984,
                25006736,
                17060676,
                22138009,
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                22855150,
                23012255,
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              ],
              "names": [
                "Colon Carcinoma",
                "Colon Carcinoma",
                "Malignant Colon Neoplasm"
              ],
              "keyword": "Hereditary cancer syndrome"
            }
          ],
          "review_stars": 0,
          "review_date": 20140904,
          "variation_id": 13961,
          "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": [
            {
              "submission_description": [
                "The val600-to-glu (V600E) mutation caused by a 1799T-A transversion in the BRAF gene was previously designated VAL599GLU (1796T-A). Kumar et al. (2003) noted that an earlier version of the BRAF sequence showed a discrepancy of 3 nucleotides in exon 1; based on the corrected sequence, they proposed a change in nucleotide numbering after nucleotide 94 (the ATG codon) by +3 and a corresponding codon change of +1.",
                "Malignant Melanoma",
                "Davies et al. (2002) identified a 1799T-A transversion in exon 15 of the BRAF gene that leads to a val600-to-glu (V600E) substitution. This mutation accounted for 92% of BRAF mutations in malignant melanoma (see 155600). The V600E mutation is an activating mutation resulting in constitutive activation of BRAF and downstream signal transduction in the MAP kinase pathway.",
                "To evaluate the timing of mutations in BRAF during melanocyte neoplasia, Pollock et al. (2003) carried out mutation analysis on microdissected melanoma and nevi samples. They observed mutations resulting in the V600E amino acid substitution in 41 (68%) of 60 melanoma metastases, 4 (80%) of 5 primary melanomas, and, unexpectedly, in 63 (82%) of 77 nevi. The data suggested that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.",
                "Lang et al. (2003) failed to find the V600E mutation as a germline mutation in 42 cases of familial melanoma studied. Their collection of families included 15 with and 24 without detected mutations in CDKN2A (600160). They did, however, find the V600E mutation in 6 (27%) of 22 samples of secondary (metastatic) melanomas studied. Meyer et al. (2003) found no V600E mutation in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients, and 106 cases with at least 1 first-degree relative suffering from other cancers. They concluded, therefore, that the common somatic BRAF mutation V600E does not contribute to polygenic or familial melanoma predisposition.",
                "Kim et al. (2003) stated that V600E, the most common of BRAF mutations, had not been identified in tumors with mutations of the KRAS gene (190070). This mutually exclusive relationship supports the hypothesis that BRAF (V600E) and KRAS mutations exert equivalent effects in tumorigenesis (Rajagopalan et al., 2002; Singer et al., 2003).",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK (600997), cyclin D1 (168461), and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Three additional patients with V600E-associated papillary thyroid also showed a partial or complete response.",
                "Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.",
                "Patients with BRAF(V600E)-positive melanomas exhibit an initial antitumor response to the RAF kinase inhibitor PLX4032, but acquired drug resistance almost invariably develops. Johannessen et al. (2010) identified MAP3K8 (191195), encoding COT (cancer Osaka thyroid oncogene) as a MAPK pathway agonist that drives resistance to RAF inhibition in BRAF(V600E) cell lines. COT activates ERK primarily through MARK/ERK (MEK)-dependent mechanisms that do not require RAF signaling. Moreover, COT expression is associated with de novo resistance in BRAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. Johannessen et al. (2010) further identified combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting.",
                "Nazarian et al. (2010) showed that acquired resistance to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS (164790) mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF (V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB upregulated tumor cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or NRAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.",
                "Poulikakos et al. (2011) identified a novel resistance mechanism for melanomas with BRAF(V600E) treated with RAF inhibitors. The authors found that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kD variant form of BRAF(V600E), p61BRAF(V600E), that lacks exons 4 through 8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) showed enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) was expressed endogenously or ectopically, ERK signaling was resistant to the RAF inhibitor. Moreover, a mutation that abolished the dimerization of p61BRAF(V600E) restored its sensitivity to vemurafenib. Finally, Poulikakos et al. (2011) identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumors of 6 of 19 patients with acquired resistance to vemurafenib. Poulikakos et al. (2011) concluded that their data supported the model that inhibition of ERK signaling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identified a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.",
                "Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.",
                "Using metabolic profiling and functional perturbations, Kaplon et al. (2013) showed that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH; 300502) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence is accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase-1 (PDK1; 602524) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase-2 (PDP2; 615499). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of oncogene-induced senescence (OIS), a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas.",
                "Sun et al. (2014) showed that 6 out of 16 BRAF(V600E)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK (176872). Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.",
                "Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E (133440) cap-binding protein, the eIF4G (600495) scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.",
                "Colorectal Carcinoma",
                "Rajagopalan et al. (2002) identified the V600E mutation in 28 of 330 colorectal tumors (see 114500) screened for BRAF mutations. In all cases the mutation was heterozygous and occurred somatically.",
                "Domingo et al. (2004) pointed out that the V600E hotspot mutation had been found in colorectal tumors that showed inherited mutation in a DNA mismatch repair (MMR) gene, such as MLH1 (120436) or MSH2 (609309). These mutations had been shown to occur almost exclusively in tumors located in the proximal colon and with hypermethylation of MLH1, the gene involved in the initial steps of development of these tumors; however, BRAF mutations were not detected in those cases with or presumed to have germline mutation in either MLH1 or MSH2. Domingo et al. (2004) studied mutation analysis of the BRAF hotspot as a possible low-cost effective strategy for genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC; 120435). The V600E mutation was found in 82 (40%) of 206 sporadic tumors with high microsatellite instability (MSI-H) but in none of 111 tested HNPCC tumors or in 45 cases showing abnormal MSH2 immunostaining. Domingo et al. (2004) concluded that detection of the V600E mutation in a colorectal MSI-H tumor argues against the presence of germline mutation in either MLH1 or MSH2, and that screening of these MMR genes can be avoided in cases positive for V600E.",
                "Lubomierski et al. (2005) analyzed 45 colorectal carcinomas with MSI and 37 colorectal tumors without MSI but with similar clinical characteristics and found that BRAF was mutated more often in tumors with MSI than without (27% vs 5%, p = 0.016). The most prevalent BRAF alteration, V600E, occurred only in tumors with MSI and was associated with more frequent MLH1 promoter methylation and loss of MLH1. The median age of patients with BRAF V600E was older than that of those without V600E (78 vs 49 years, p = 0.001). There were no BRAF alterations in patients with germline mutations of mismatch repair genes. Lubomierski et al. (2005) concluded that tumors with MSI caused by epigenetic MLH1 silencing have a mutational background distinct from that of tumors with genetic loss of mismatch repair, and suggested that there are 2 genetically distinct entities of microsatellite unstable tumors.",
                "Tol et al. (2009) detected a somatic V600E mutation in 45 (8.7%) of 519 metastatic colorectal tumors. Patients with BRAF-mutated tumors had significantly shorter median progression-free and median overall survival compared to patients with wildtype BRAF tumors, regardless of the use of cetuximab. Tol et al. (2009) suggested that the BRAF mutation may be a negative prognostic factor in these patients.",
                "Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harboring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of this limited therapeutic effect in BRAF(V600E) mutant colon cancer, Prahallad et al. (2012) performed an RNA interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. They reported that blockade of the epidermal growth factor receptor (EGFR; 131550) shows strong synergy with BRAF(V600E) inhibition. Prahallad et al. (2012) found in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, Prahallad et al. (2012) found that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, Prahallad et al. (2012) found that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Prahallad et al. (2012) concluded that BRAF(V600E) mutant colon cancers (approximately 8 to 10% of all colon cancers) might benefit from combination therapy consisting of BRAF and EGFR inhibitors.",
                "Gala et al. (2014) identified the BRAF V600E mutation in 18 of 19 sessile serrated adenomas from 19 unrelated patients with sessile serrated polyposis cancer syndrome (SSPCS; 617108).",
                "Papillary Thyroid Carcinoma",
                "Kimura et al. (2003) identified the V600E mutation in 28 (35.8%) of 78 papillary thyroid cancers (PTC; see 188550); it was not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). RET (see 164761)/PTC mutations and RAS (see 190020) mutations were each identified in 16.4% of PTCs, but there was no overlap in the 3 mutations. Kimura et al. (2003) concluded that thyroid cell transformation to papillary cancer takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway.",
                "Xing et al. (2004) studied various thyroid tumor types for the most common BRAF mutation, 1799T-A, by DNA sequencing. They found a high and similar frequency (45%) of the 1799T-A mutation in 2 geographically distinct papillary thyroid cancer patient populations, 1 composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, Xing et al. (2004) found BRAF mutations in only 20% of anaplastic thyroid cancers and in no medullary thyroid cancers or benign thyroid hyperplasia. They also confirmed previous reports that the BRAF 1799T-A mutation did not occur in benign thyroid adenomas or follicular thyroid cancers. They concluded that frequent occurrence of BRAF mutation is associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation.",
                "Nikiforova et al. (2003) analyzed 320 thyroid tumors and 6 anaplastic carcinoma cell lines and detected BRAF mutations in 45 papillary carcinomas (38%), 2 poorly differentiated carcinomas (13%), 3 (10%) anaplastic carcinomas (10%), and 5 thyroid anaplastic carcinoma cell lines (83%) but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-to-A transversion at nucleotide 1799. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well differentiated and dedifferentiated components. The authors concluded that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas, and that they are associated with distinct phenotypic and biologic properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.",
                "Hypothesizing that childhood thyroid carcinomas may be associated with a different prevalence of the BRAF 1799T-A mutation compared with adult cases, Kumagai et al. (2004) examined 31 cases of Japanese childhood thyroid carcinoma and an additional 48 cases of PTC from Ukraine, all of whom were less than 17 years of age at the time of the Chernobyl accident. The BRAF 1799T-A mutation was found in only 1 of 31 Japanese cases (3.4%) and in none of the 15 Ukrainian cases operated on before the age of 15 years, although it was found in 8 of 33 Ukrainian young adult cases (24.2%). Kumagai et al. (2004) concluded that the BRAF 1799T-A mutation is uncommon in childhood thyroid carcinomas.",
                "Puxeddu et al. (2004) found the V600E substitution in 24 of 60 PTCs (40%) but in none of 6 follicular adenomas, 5 follicular carcinomas, or 1 anaplastic carcinoma. Nine of the 60 PTCs (15%) presented expression of a RET/PTC rearrangement. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). No link could be detected between expression of BRAF V600E and age at diagnosis, gender, dimension, local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, or multifocality of the disease. The authors concluded that these data clearly confirmed that BRAF V600E was the most common genetic alteration found to that time in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.",
                "Xing et al. (2004) demonstrated detection of the 1799T-A mutation on thyroid cytologic specimens from fine needle aspiration biopsy (FNAB). Prospective analysis showed that 50% of the nodules that proved to be PTCs on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings.",
                "Xing et al. (2005) studied the relationships between the BRAF V600E mutation and clinicopathologic outcomes, including recurrence, in 219 PTC patients. The authors concluded that in patients with PTC, BRAF mutation is associated with poorer clinicopathologic outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.",
                "In a series of 52 classic PTCs, Porra et al. (2005) found that low SLC5A8 (608044) expression was highly significantly associated with the presence of the BRAF 1799T-A mutation. SLC5A8 expression was selectively downregulated (40-fold) in PTCs of classical form; methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of classic PTCs and in about 20% of other PTCs. Porra et al. (2005) concluded that their data identified a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the 1799T-A point mutation of the BRAF gene in the classic PTC subtype of thyroid carcinomas.",
                "Vasko et al. (2005) studied the relationship between the BRAF 1799T-A mutation and lymph node metastasis of PTC by examining the mutation in both the primary tumors and their paired lymph node metastases. Their findings indicated that the high prevalence of BRAF mutation in lymph node-metastasized PTC tissues from BRAF mutation-positive primary tumors and the possible de novo formation of BRAF mutation in lymph node-metastasized PTC were consistent with a role of BRAF mutation in facilitating the metastasis and progression of PTC in lymph nodes.",
                "In a patient with congenital hypothyroidism and long-standing goiter due to mutation in the thyroglobulin gene (see TG, 188540; and TDH3, 274700), who was also found to have multifocal follicular carcinoma of the thyroid, Hishinuma et al. (2005) identified somatic heterozygosity for the V600E mutation in the BRAF gene in the cancerous thyroid tissue.",
                "Liu et al. (2007) used BRAF siRNA to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. They found that the V600E mutation not only initiates PTC but also maintains the proliferation, transformation, and tumorigenicity of PTC cells harboring the BRAF mutation, and that the growth of tumors derived from such cells continues to depend on the V600E mutation.",
                "Jo et al. (2006) found that of 161 PTC patients, 102 (63.4%) had the BRAF V600E mutation and that these patients had significantly larger tumor sizes and significantly higher expression of vascular endothelial growth factor (VEGF; 192240) compared to patients without this mutation. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. Jo et al. (2006) concluded that the relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.",
                "Durante et al. (2007) found that the BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. They noted that this effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mutation PTCs.",
                "Lupi et al. (2007) found a BRAF mutation in 219 of 500 cases (43.8%) of PTC. The most common BRAF mutation, V600E, was found in 214 cases (42.8%). BRAF V600E was associated with extrathyroidal invasion (p less than 0.0001), multicentricity (p = 0.0026), presence of nodal metastases (p = 0.0009), class III versus classes I and II (p less than 0.00000006), and absence of tumor capsule (p less than 0.0001), in particular, in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (p = 0.0005) with the BRAF V600E mutation. The authors concluded that the BRAF V600E mutation is associated with high-risk PTC and, in particular, in follicular variant with invasive tumor growth.",
                "Flaherty et al. (2010) reported complete or partial regression of V600E-associated papillary thyroid cancer in 3 patients treated with an inhibitor (PLX4032) specific to the V600E mutation.",
                "Nonseminomatous Germ Cell Tumors",
                "In 3 (9%) of 32 nonseminomatous germ cell tumors (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma, Sommerer et al. (2005) identified the activating 1796T-A mutation in the BRAF gene; the mutation was present within the embryonic carcinoma component.",
                "Astrocytoma",
                "Pfister et al. (2008) identified a somatic V600E mutation in 4 (6%) of 66 pediatric low-grade astrocytomas (see 137800). Thirty (45%) of the 66 tumors had a copy number gain spanning the BRAF locus, indicating a novel mechanism of MAPK (176948) pathway activation in these tumors.",
                "Role in Neurodegeneration",
                "Mass et al. (2017) hypothesized that a somatic BRAF(V600E) mutation in the erythromyeloid lineage may cause neurodegeneration. Mass et al. (2017) showed that mosaic expression of BRAF(V600E) in mouse erythromyeloid progenitors results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioral signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss, and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. Mass et al. (2017) suggested that the results identified the fetal precursors of tissue-resident macrophages as a potential cell of origin for histiocytoses and demonstrated that a somatic mutation in the erythromyeloid progenitor lineage in mice can drive late-onset neurodegeneration.",
                "Variant Function",
                "Brady et al. (2014) showed that decreasing the levels of CTR1 (603085), or mutations in MEK1 (176872) that disrupt copper binding, decreased BRAF(V600E)-driven signaling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 (602520) chimera that phosphorylated ERK1/2 independently of copper or an active ERK2 restored the tumor growth of murine cells lacking Ctr1. Copper chelators used in the treatment of Wilson disease (277900) decreased tumor growth of human or murine cells that were either transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Brady et al. (2014) concluded that copper chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.",
                "Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 (612694) and/or CTU2 (617057) synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation."
              ],
              "review_description": "Pathogenic",
              "submitter_name": "OMIM",
              "review_date": 20140904,
              "origin": "somatic",
              "method": "literature only",
              "submitter_date": 20220317,
              "diseases": [
                {
                  "normalized_disease": [
                    "Colorectal Cancer"
                  ],
                  "normalized_cancer": [
                    "COLORECTAL CANCER, SOMATIC"
                  ],
                  "names": [
                    "Colorectal Cancer"
                  ]
                }
              ],
              "date_updated": 20220328,
              "clinical_significance": [
                "Pathogenic"
              ],
              "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_status": "no assertion criteria provided",
              "accession_id": "SCV000035248"
            }
          ]
        },
        {
          "accession_id": "RCV000080903",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "criteria provided, multiple submitters, no conflicts",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND not provided",
          "date_created": 20140117,
          "diseases": [
            {
              "symbols": {
                "medgen": "C3661900"
              },
              "names": [
                "Not Provided",
                "None Provided"
              ]
            }
          ],
          "review_stars": 2,
          "review_date": 20140711,
          "variation_id": 13961,
          "submission_description": [],
          "submissions": [
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Clinical Genetics and Genomics, Karolinska University Hospital",
              "review_date": 20140711,
              "origin": "germline",
              "method": "clinical testing",
              "submitter_date": 20201126,
              "diseases": [
                {
                  "names": [
                    "Not Provided"
                  ]
                }
              ],
              "date_updated": 20201212,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "criteria provided, single submitter",
              "accession_id": "SCV001450230"
            },
            {
              "submission_description": [],
              "review_description": "Pathogenic",
              "submitter_name": "Eurofins Ntd Llc (ga)",
              "review_date": 20131008,
              "origin": "germline",
              "method": "clinical testing",
              "submitter_date": 20180919,
              "diseases": [
                {
                  "names": [
                    "Not Provided"
                  ]
                }
              ],
              "date_updated": 20150629,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "criteria provided, single submitter",
              "accession_id": "SCV000112810"
            },
            {
              "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System",
              "submission_description": [],
              "review_description": "Uncertain significance",
              "origin": "unknown",
              "method": "clinical testing",
              "submitter_date": 20210331,
              "diseases": [
                {
                  "names": [
                    "Not Provided"
                  ]
                }
              ],
              "date_updated": 20210413,
              "clinical_significance": [
                "Uncertain significance"
              ],
              "review_status": "no assertion criteria provided",
              "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_description": "Pathogenic",
              "origin": "somatic",
              "method": "clinical testing",
              "submitter_date": 20211006,
              "diseases": [
                {
                  "symbols": {
                    "medgen": "CN517202"
                  }
                }
              ],
              "date_updated": 20211016,
              "clinical_significance": [
                "Pathogenic"
              ],
              "review_status": "no assertion criteria provided",
              "accession_id": "SCV001962698"
            }
          ],
          "variant_id": 10190071404531360004
        },
        {
          "accession_id": "RCV000037936",
          "allele_id": 29000,
          "review_description": "Pathogenic",
          "review_status": "no assertion criteria provided",
          "clinical_significance": [
            "Pathogenic"
          ],
          "title": "NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Non-small cell lung carcinoma",
          "date_created": 20130503,
          "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"
            }
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          "value": 1
        },
        {
          "key": "MBN",
          "value": 1
        },
        {
          "key": "IPMN",
          "value": 1
        },
        {
          "key": "IHCH",
          "value": 1
        },
        {
          "key": "HNSC",
          "value": 1
        },
        {
          "key": "GNC",
          "value": 1
        },
        {
          "key": "GIST",
          "value": 1
        },
        {
          "key": "APE",
          "value": 1
        },
        {
          "key": "APAD",
          "value": 1
        }
      ],
      "cancer_name": [
        {
          "key": "Cutaneous Melanoma",
          "value": 295
        },
        {
          "key": "Papillary Thyroid Cancer",
          "value": 292
        },
        {
          "key": "Colon Adenocarcinoma",
          "value": 54
        },
        {
          "key": "Colorectal Adenocarcinoma",
          "value": 47
        },
        {
          "key": "Lung Adenocarcinoma",
          "value": 33
        },
        {
          "key": "Melanoma of Unknown Primary",
          "value": 14
        },
        {
          "key": "Anaplastic Thyroid Cancer",
          "value": 14
        },
        {
          "key": "Poorly Differentiated Thyroid Cancer",
          "value": 9
        },
        {
          "key": "Glioblastoma Multiforme",
          "value": 8
        },
        {
          "key": "Plasma Cell Myeloma",
          "value": 6
        },
        {
          "key": "Mucinous Adenocarcinoma of the Colon and Rectum",
          "value": 5
        },
        {
          "key": "Pancreatic Adenocarcinoma",
          "value": 5
        },
        {
          "key": "Cancer of Unknown Primary",
          "value": 5
        },
        {
          "key": "Erdheim-Chester Disease",
          "value": 3
        },
        {
          "key": "Cholangiocarcinoma",
          "value": 3
        },
        {
          "key": "High-Grade Glioma, NOS",
          "value": 3
        },
        {
          "key": "High-Grade Neuroendocrine Carcinoma of the Colon and Rectum",
          "value": 3
        },
        {
          "key": "Pancreatic Neuroendocrine Tumor",
          "value": 3
        },
        {
          "key": "Rectal Adenocarcinoma",
          "value": 3
        },
        {
          "key": "Low-Grade Glioma, NOS",
          "value": 3
        },
        {
          "key": "Bladder Urothelial Carcinoma",
          "value": 2
        },
        {
          "key": "Langerhans Cell Histiocytosis",
          "value": 2
        },
        {
          "key": "Low-Grade Serous Ovarian Cancer",
          "value": 2
        },
        {
          "key": "Anaplastic Pleomorphic Xanthoastrocytoma",
          "value": 2
        },
        {
          "key": "Neuroblastoma",
          "value": 2
        },
        {
          "key": "Acral Melanoma",
          "value": 2
        },
        {
          "key": "Papillary Renal Cell Carcinoma",
          "value": 1
        },
        {
          "key": "Uterine Leiomyosarcoma",
          "value": 1
        },
        {
          "key": "Mature B-Cell Neoplasms",
          "value": 1
        },
        {
          "key": "Intrahepatic Cholangiocarcinoma",
          "value": 1
        },
        {
          "key": "Intraductal Papillary Mucinous Neoplasm",
          "value": 1
        },
        {
          "key": "Head and Neck Squamous Cell Carcinoma",
          "value": 1
        },
        {
          "key": "Gastrointestinal Stromal Tumor",
          "value": 1
        },
        {
          "key": "Gangliocytoma",
          "value": 1
        },
        {
          "key": "Breast Mixed Ductal and Lobular Carcinoma",
          "value": 1
        },
        {
          "key": "Appendiceal Adenocarcinoma",
          "value": 1
        },
        {
          "key": "Anaplastic Ependymoma",
          "value": 1
        }
      ],
      "cancer_type": [
        {
          "key": "Thyroid Cancer",
          "value": 315
        },
        {
          "key": "Melanoma",
          "value": 311
        },
        {
          "key": "Colorectal Cancer",
          "value": 109
        },
        {
          "key": "Non-Small Cell Lung Cancer",
          "value": 33
        },
        {
          "key": "Glioma",
          "value": 17
        },
        {
          "key": "Pancreatic Cancer",
          "value": 9
        },
        {
          "key": "Mature B-Cell Neoplasms",
          "value": 7
        },
        {
          "key": "Cancer of Unknown Primary",
          "value": 5
        },
        {
          "key": "Histiocytosis",
          "value": 5
        },
        {
          "key": "Hepatobiliary Cancer",
          "value": 4
        },
        {
          "key": "Gastrointestinal Neuroendocrine Tumor",
          "value": 3
        },
        {
          "key": "Bladder Cancer",
          "value": 2
        },
        {
          "key": "Peripheral Nervous System",
          "value": 2
        },
        {
          "key": "Ovarian Cancer",
          "value": 2
        },
        {
          "key": "Head and Neck Cancer",
          "value": 1
        },
        {
          "key": "Gastrointestinal Stromal Tumor",
          "value": 1
        },
        {
          "key": "CNS Cancer",
          "value": 1
        },
        {
          "key": "Breast Cancer",
          "value": 1
        },
        {
          "key": "Renal Cell Carcinoma",
          "value": 1
        },
        {
          "key": "Appendiceal Cancer",
          "value": 1
        },
        {
          "key": "Uterine Sarcoma",
          "value": 1
        }
      ],
      "tissue_type": [
        {
          "key": "Thyroid",
          "value": 315
        },
        {
          "key": "Skin",
          "value": 311
        },
        {
          "key": "Bowel",
          "value": 113
        },
        {
          "key": "Lung",
          "value": 33
        },
        {
          "key": "CNS/Brain",
          "value": 18
        },
        {
          "key": "Pancreas",
          "value": 9
        },
        {
          "key": "Lymphoid",
          "value": 7
        },
        {
          "key": "Myeloid",
          "value": 5
        },
        {
          "key": "Other",
          "value": 5
        },
        {
          "key": "Biliary Tract",
          "value": 4
        },
        {
          "key": "Bladder/Urinary Tract",
          "value": 2
        },
        {
          "key": "Peripheral Nervous System",
          "value": 2
        },
        {
          "key": "Ovary/Fallopian Tube",
          "value": 2
        },
        {
          "key": "Kidney",
          "value": 1
        },
        {
          "key": "Head and Neck",
          "value": 1
        },
        {
          "key": "Soft Tissue",
          "value": 1
        },
        {
          "key": "Breast",
          "value": 1
        },
        {
          "key": "Uterus",
          "value": 1
        }
      ]
    }
  ]
}