Gene Variant Detail

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Gene BRAF
Variant G596R
Impact List missense
Protein Effect loss of function - predicted
Gene Variant Descriptions BRAF G596R lies within the protein kinase domain of the Braf protein (UniProt.org). G596R results in activation of Erk in the presence of CRAF (PMID: 19735675, PMID: 28783719, PMID: 18697864) and in another study demonstrates similar cell proliferation and viability levels to wild-type Braf (PMID: 29533785), but 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 (PMID: 19735675, PMID: 28783719), and therefore, is predicted to lead to a loss of Braf protein function.
Associated Drug Resistance
Category Variants Paths

BRAF mutant BRAF G596X BRAF G596R

BRAF mutant BRAF inact mut BRAF G596R

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Transcript NM_004333.6
gDNA chr7:g.140753349C>G
cDNA c.1786G>C
Protein p.G596R
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001378474.1 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
XM_005250045 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_001378467.1 chr7:g.140753358C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_004333.6 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_004333.5 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_001378468.1 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_001354609.1 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_001354609.2 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38
NM_004333 chr7:g.140753349C>G c.1786G>C p.G596R RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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 PLX8394 Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells harboring BRAF G596R demonstrated sensitivity to PLX8394 treatment in culture (PMID: 30559419). 30559419