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Gene | BRAF |
Variant | D594G |
Impact List | missense |
Protein Effect | loss of function - predicted |
Gene Variant Descriptions | BRAF D594G lies within the protein kinase domain of the Braf protein (UniProt.org). D594G demonstrates increased transforming ability in one of two cell lines in culture (PMID: 29533785), however, results in impaired Braf kinase activity, but leads to increased activation of Erk signaling through Craf in cell culture (PMID: 18794803, PMID: 28783719), and also demonstrates Craf activation similar to wild-type Braf, but with enhanced dimerization and the ability to bypass autoinhibitory autophosphorylation in in vitro assays (PMID: 31929109), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, is predicted to lead to a loss of Braf protein function. |
Associated Drug Resistance | Y |
Category Variants Paths |
BRAF mutant BRAF D594X BRAF D594G BRAF mutant BRAF inact mut BRAF D594G |
Transcript | NM_004333.6 |
gDNA | chr7:g.140753354T>C |
cDNA | c.1781A>G |
Protein | p.D594G |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_001354609.1 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_004333.6 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_001354609.2 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
XM_005250045 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_001378474.1 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_004333.5 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_004333 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
NM_001378468.1 | chr7:g.140753354T>C | c.1781A>G | p.D594G | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
BRAF D594G NRAS G12D | melanoma | sensitive | AZ628 | Preclinical - Cell culture | Actionable | In a preclinical study, AZ628 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | sensitive | TAK-632 | Preclinical - Cell culture | Actionable | In a preclinical study, TAK-632 inhibited proliferation of melanoma cell lines harboring both BRAF D594G and NRAS G12D in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | PLX7904 | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to PLX7904 in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Zelboraf (vemurafenib) in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | decreased response | Dabrafenib | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring both BRAF D594G and NRAS G12D demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 27523909). | 27523909 |
BRAF D594G NRAS G12D | melanoma | sensitive | Binimetinib + Encorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Mektovi (binimetinib) and Braftovi (encorafenib) resulted in a synergistic effect in melanoma cells harboring BRAF D594G and NRAS G12D, with decreased cell viability and Erk phosphorylation and increased apoptosis in culture (PMID: 35385748). | 35385748 |