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|Protein Effect||loss of function - predicted|
|Gene Variant Descriptions||BRAF G596R lies within the protein kinase domain of the Braf protein, within the DFG motif (PMID: 19735675). G596R results in impaired Braf kinase activity and decreased Mek and Erk phosphorylation, including in the presence of BRAF V600E, is not transforming in culture and does not promote tumor formation in mouse models, but results in activation of Erk in the presence of CRAF (PMID: 19735675, PMID: 28783719), however, in another study demonstrates similar cell proliferation and viability levels to wild-type Braf (PMID: 29533785), and is predicted to confer a loss of function to the Braf protein.|
|Associated Drug Resistance|
|Transcript||gDNA||cDNA||Protein||Source Database||Genome Build|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF G596R||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 G596R, and enrollment in this cohort was discontinued (PMID: 31959346; NCT02304809).||31959346|
|BRAF G596R||colorectal cancer||predicted - sensitive||RMC-4550||Preclinical - Cell culture||Actionable||In a preclinical study, RMC-4550 inhibited Erk phosphorylation and proliferation of colorectal cancer cells harboring BRAF G596R in culture (PMID: 30104724).||30104724|
|BRAF G596R||colorectal cancer||resistant||Vemurafenib||Preclinical - Cell culture||Actionable||In a preclinical study, Zelboraf (vemurafenib) did not reduce activation of Erk and Mek in a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28783719).||28783719|
|BRAF G596R||Advanced Solid Tumor||no benefit||Vemurafenib||Clinical Study - Cohort||Actionable||In a Phase II trial (MyPathway), Zelboraf (vemurafenib) treatment resulted in an objective response in only 4% (1/23) of patient with advanced solid tumors harboring non-V600 BRAF mutations, 1 of the non-responding patients harbored BRAF G596R (PMID: 29320312; NCT02091141).||29320312|
|BRAF G596R||colorectal cancer||sensitive||Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, Mekinist (trametinib) reduced Erk signaling and inhibited proliferation of a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28783719).||28783719|
|BRAF G596R||colorectal cancer||sensitive||Dabrafenib + Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) resulted in decreased proliferation and increased apoptosis, and enhanced ERK inhibition compared to either agent alone in a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28947956).||28947956|
|BRAF G596R PIK3CA E545K||colorectal cancer||sensitive||Neratinib||Preclinical||Actionable||In a preclinical study, Nerlynx (neratinib) inhibited growth of colorectal cancer cells harboring both BRAF G596R and PIK3CA E545K in culture (PMID: 26243863).||26243863|
|BRAF G596R PTPN11 E76K||colorectal cancer||resistant||RMC-4550||Preclinical - Cell culture||Actionable||In a preclinical study, expression of PTPN11 E76K in colorectal cancer cells harboring BRAF G596R abolished their sensitivity to RMC-4550-induced inhibition of Erk phosphorylation and proliferation in culture (PMID: 30104724).||30104724|