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Gene | BRAF |
Variant | G469V |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | BRAF G469V is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469V results in increased Braf kinase activity and activation of downstream MEK and ERK in cell culture (PMID: 28947956, PMID: 26343582, PMID: 28783719), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785). |
Associated Drug Resistance | |
Category Variants Paths |
BRAF mutant BRAF act mut BRAF G469V BRAF mutant BRAF G469X BRAF G469V |
Transcript | NM_004333.6 |
gDNA | chr7:g.140781602C>A |
cDNA | c.1406G>T |
Protein | p.G469V |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_004333.6 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001378468.1 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001354609.2 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001378467.1 | chr7:g.140781611C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001378474.1 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
XM_047420769.1 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001378470.1 | chr7:g.140778000C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_001354609.1 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_004333 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
NM_004333.5 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
XM_005250045 | chr7:g.140781602C>A | c.1406G>T | p.G469V | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
BRAF G469V | Advanced Solid Tumor | resistant | Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G469V (PMID: 26343582). | 26343582 |
BRAF G469V | lung non-small cell carcinoma | predicted - sensitive | Sorafenib | Case Reports/Case Series | Actionable | In a clinical case study, a patient with synchronous BRAF wild-type hepatocellular carcinoma (HCC) and non-small cell lung cancer harboring BRAF G469V demonstrated a partial response in primary lung lesions, complete response in the lung metastasis, and stability of the HCC following treatment with Nexavar (sorafenib) (PMID: 27388325). | 27388325 |
BRAF G469V | melanoma | no benefit | Encorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Braftovi (encorafenib) did not inhibit ERK phosphorylation or proliferation of a melanoma cell line harboring BRAF G469V (PMID: 29903896). | 29903896 |
BRAF G469V | lung non-small cell carcinoma | no benefit | Vemurafenib | Case Reports/Case Series | Actionable | In a Phase II trial, Zelboraf (vemurafenib) treatment did not result in response in the cohort of 15 non-small cell lung cancer patients with non-V600 BRAF mutations, which included 1 patient harboring BRAF G469V, and enrollment in this cohort was discontinued (PMID: 31959346; NCT02304809). | 31959346 |
BRAF G469V | osteosarcoma | no benefit | Trametinib | Case Reports/Case Series | Actionable | In a Phase II trial (NCI-MATCH), Mekinist (trametinib) treatment did not demonstrate clinical activity in patients with advanced solid tumors or lymphoma harboring BRAF fusion or non-V600 mutations, resulted in progressive disease in a patient with osteosarcoma of the renal pelvis harboring BRAF G469V (PMID: 31924734; NCT02465060). | 31924734 |
BRAF G469V | lung adenocarcinoma | no benefit | Dabrafenib + Trametinib | Case Reports/Case Series | Actionable | In a clinical case study, a previously treated lung adenocarcinoma patient harboring BRAF G469V demonstrated progression after 9 weeks of treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) (PMID: 32540409). | 32540409 |
BRAF G469V | colorectal cancer | not predictive | Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab | Case Reports/Case Series | Actionable | In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in a partial response with progression-free survival of 18.9 months in a patient with metastatic colorectal cancer harboring BRAF G469V (PMID: 31515458). | 31515458 |
BRAF G469V | colorectal cancer | not predictive | Cetuximab + Irinotecan | Case Reports/Case Series | Actionable | In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease with progression-free survival of 10.9 months in a patient with metastatic colorectal cancer harboring BRAF G469V (PMID: 31515458). | 31515458 |
BRAF G469V | lung adenocarcinoma | sensitive | Gefitinib | Preclinical - Patient cell culture | Actionable | In a preclinical study, Iressa (gefitinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945). | 34648945 |
BRAF G469V | lung adenocarcinoma | sensitive | Afatinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Gilotrif (afatinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945). | 34648945 |
BRAF G469V | lung adenocarcinoma | sensitive | Osimertinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Tagrisso (osimertinib) treatment inhibited viability of cells derived from a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring BRAF G469V in culture and led to inhibition of tumor growth in a patient-derived xenograft (PDX) model (PMID: 34648945). | 34648945 |