BRAF G596R
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 impaired Braf kinase activity, but leads to Craf-dependent activation of Erk in culture (PMID: 19735675, PMID: 28783719, PMID: 18697864), demonstrates similar cell proliferation and viability levels to wild-type Braf (PMID: 29533785), is not transforming in culture, and does not promote tumor formation in mouse models (PMID: 19735675), 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
XM_005250045 chr7:g.140753349C>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_001378474.1 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_004333 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_001378467.1 chr7:g.140753358C>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_004333.5 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
BRAF G596R colorectal cancer sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 40333694). 40333694