Gene Variant Detail

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Gene BRAF
Variant V600K
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions BRAF V600K (previously reported as V599) lies within the activation segment of the kinase domain of the Braf protein (PMID: 15035987). V600K confers a gain of function to the Braf protein as demonstrated by increased kinase activity, downstream signaling, and the ability to transform cells in vitro (PMID: 15035987, PMID: 29533785).
Associated Drug Resistance
Category Variants Paths

BRAF mutant BRAF act mut BRAF V600E/K BRAF V600K

BRAF mutant BRAF V600X BRAF V600E/K BRAF V600K

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Transcript NM_004333.6
gDNA chr7:g.140753336_140753337delGTinsAA
cDNA c.1798_1799delGTinsAA
Protein p.V600K
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001354609.2 chr7:g.140753336_140753337delGTinsAA c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
XM_005250045 chr7:g.140753336_140753337delACinsTT c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
NM_001378474.1 chr7:g.140753336_140753337delGTinsAA c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
NM_004333 chr7:g.140753336_140753337delACinsTT c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
NM_004333.5 chr7:g.140753336_140753337delACinsTT c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
NM_001378468.1 chr7:g.140753336_140753337delGTinsAA c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38
NM_004333.6 chr7:g.140753336_140753337delGTinsAA c.1798_1799delGTinsAA p.V600K RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600K skin melanoma sensitive Dabrafenib Guideline Actionable Tafinlar (dabrafenib) therapy is included in guidelines for cutaneous melanoma patients with unresectable or metastatic disease harboring BRAF V600 activating mutations, such as BRAF V600K, in cases where BRAF/MEK inhibitor combination therapy is contraindicated (NCCN.org). detail...
BRAF V600K melanoma sensitive GSK2126458 Preclinical Actionable In a preclinical study, Omipalisib (GSK2126458) inhibited the growth of melanoma cell lines harboring BRAF V600K in culture (PMID: 22389471). 22389471
BRAF V600K melanoma sensitive Cobimetinib + Vemurafenib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (coBRIM) that supported FDA approval, treatment with the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) resulted in an improved progression-free survival of 12.3 months, compared to 7.2 months with Zelboraf (vemurafenib) plus placebo, among patients with BRAF V600-mutated metastatic melanoma, and BRAF V600E and BRAF V600K are on the companion diagnostic (PMID: 27480103; NCT01689519). detail... 27480103 detail...
BRAF V600K melanoma sensitive Dabrafenib + Trametinib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (COMBI-v) that supported FDA approval, the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in an improved overall survival rate at 12 months (72% vs 65%, HR=0.69, p=0.005), median progression-free survival (11.4 vs 7.3 months, HR=0.56, p<0.001), and objective response rate (64% vs 51%, p<0.001) compared to Zelboraf (vemurafenib) in melanoma patients harboring BRAF V600E or V600K (PMID: 25399551; NCT01597908). detail... 25399551 detail...
BRAF V600K melanoma sensitive Trametinib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (METRIC) that supported FDA approval, Mekinist (trametinib) treatment, as compared to Deticine (dacarbazine) or Taxol (paclitaxel) treatment, resulted in improved progression-free survival of 4.8 months versus 1.5 months and an overall six month survival rate of 81% versus 67% in patients with BRAF V600E/K-positive metastatic melanoma (PMID: 22663011; NCT01245062). 22663011 detail... detail...
BRAF V600K skin melanoma sensitive Vemurafenib Guideline Actionable Zelboraf (vemurafenib) therapy is included in guidelines for cutaneous melanoma patients with unresectable or metastatic disease harboring BRAF V600 activating mutations, such as BRAF V600K, in cases where BRAF/MEK inhibitor combination therapy is contraindicated (NCCN.org). detail...
BRAF V600K melanoma predicted - sensitive Pembrolizumab Clinical Study - Cohort Actionable In a retrospective analysis, patients with melanoma harboring BRAF V600K (n=19) had increased tumor mutational burden and greater response rates (53% vs. 29%, p=0.059), progression-free survival (19 vs. 2.7 months, p=0.049), and overall survival (20.4 vs. 11.7 months, p=0.081) relative to patients with BRAF V600E (n=84) when treated with Keytruda (pembrolizumab) (n=17 and 62 for BRAF V600K and V600E, respectively) or Opdivo (nivolumab) (n=2 and 22 for BRAF V600K and V600E, respectively) (PMID: 30630828). 30630828
BRAF V600K melanoma predicted - sensitive Nivolumab Clinical Study - Cohort Actionable In a retrospective analysis, patients with melanoma harboring BRAF V600K (n=19) had increased tumor mutational burden and greater response rates (53% vs. 29%, p=0.059), progression-free survival (19 vs. 2.7 months, p=0.049), and overall survival (20.4 vs. 11.7 months, p=0.081) relative to patients with BRAF V600E (n=84) when treated with Keytruda (pembrolizumab) (n=17 and 62 for BRAF V600K and V600E, respectively) or Opdivo (nivolumab) (n=2 and 22 for BRAF V600K and V600E, respectively) (PMID: 30630828). 30630828
BRAF V600K melanoma sensitive Binimetinib + Encorafenib FDA approved - On Companion Diagnostic Actionable In a Phase III (COLUMBUS) trial that supported FDA approval, Braftovi (encorafenib) in combination with Mektovi (binimetinib) demonstrated improved tolerability profile and efficacy, resulted in a progression-free survival of 14.9 months in patients with advanced melanoma harboring BRAF V600E/K mutations, comparing to 7.3 months in the Zelboraf (vemurafenib) group (HR=0.54, p<0.0001) (PMID: 29573941; NCT01909453) and both BRAF V600E and BRAF V600K are on the companion diagnostic. 29573941 detail... detail... detail...
BRAF V600K melanoma sensitive Binimetinib + Encorafenib FDA approved - On Companion Diagnostic Actionable In a Phase III (COLUMBUS) trial that supported FDA approval, Braftovi (encorafenib) in combination with Mektovi (binimetinib) resulted in a median overall survival (OS) of 33.6 months, a 1-year OS rate of 77.5%, and a 2-year OS rate of 57.7% in patients with advanced melanoma harboring BRAF V600E/K mutations compared to a median OS of 16.9 months and 1- and 2-year OS rates of 63.1% and 43.2%, respectively, in the Zelboraf (vemurafenib) treated group (PMID: 30219628; NCT01909453). detail... 30219628 detail... detail...
BRAF V600K skin melanoma sensitive Cobimetinib + Vemurafenib Guideline Actionable Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy is included in cutaneous melanoma guidelines for patients with metastatic or unresectable disease harboring a BRAF V600 activating mutation (NCCN.org). detail...
BRAF V600K skin melanoma sensitive Dabrafenib + Trametinib Guideline Actionable Tafinlar (dabrafenib) and Mekinist (trametinib) combination therapy is included in guidelines for melanoma patients harboring a BRAF V600 mutation, such as BRAF V600K, as neoadjuvant or adjuvant therapy for stage III disease and as systemic therapy for patients with unresectable or metastatic disease (NCCN.org). detail...
BRAF V600K skin melanoma sensitive Binimetinib + Encorafenib Guideline Actionable Braftovi (encorafenib) in combination with Mektovi (binimetinib) is included in guidelines as first-line and second-line therapy for patients with metastatic or unresectable cutaneous melanoma harboring BRAF V600E or V600K mutations (PMID: 30959471; NCCN.org). 30959471 detail...
BRAF V600K lung non-small cell carcinoma predicted - sensitive Vemurafenib Case Reports/Case Series Actionable In a Phase II trial, Zelboraf (vemurafenib) treatment resulted in a objective response rate of 44.8% (43/96), median duration of response of 6.4 months, median progression-free survival (PFS) of 5.2 months, and median overall survival of 10 months in non-small cell lung cancer patients with BRAF V600 mutations, with a PFS of 2.1 and 6.8 months in the 2 patients harboring BRAF V600K (PMID: 31959346; NCT02304809). 31959346
BRAF V600K melanoma predicted - sensitive Dabrafenib + Pembrolizumab + Trametinib Phase II Actionable In a Phase II trial (IMPemBra), Keytruda (pembrolizumab) in combination with short-term or intermittent Tafinlar (dabrafenib) plus Mekinist (trametinib) resulted in improved median progression-free survival compared to Keytruda (pembrolizumab) monotherapy (27.0 vs 10.6 mo, p=0.13) in patients with treatment-naive advanced melanoma harboring BRAF V600E (n=26) or V600K (n=6) mutations (J Clin Oncol 38: 2020 (suppl; abstr 10021); NCT02625337). detail...
BRAF V600K colon cancer sensitive PLX8394 Preclinical - Cell culture Actionable In a preclinical study, PLX8394 treatment inhibited Erk signaling and reduced proliferation of colon cancer cells harboring BRAF V600K in culture (PMID: 30559419). 30559419
BRAF V600K melanoma no benefit Cobimetinib + Pembrolizumab + Vemurafenib Phase I Actionable In a Phase I trial, combination of Cotellic (cobimetinib), Zelboraf (vemurafenib), and Keytruda (pembrolizumab) resulted in unreached median progression-free survival and overall survival in patients with advanced melanoma harboring BRAF V600E or V600K mutations, however, the trial was closed due to high incidence of dose-limiting toxicity and decreased health utility at 1 year (J Clin Oncol 39, no. 15_suppl, abstract e21506; NCT02818023). detail...
BRAF V600K skin melanoma sensitive Dabrafenib + Pembrolizumab + Trametinib Guideline Actionable Tafinlar (dabrafenib) plus Mekinist (trametinib) in combination with an immune checkpoint inhibitor, such as Keytruda (pembrolizumab), is included in guidelines as second-line or subsequent therapy (category 2A) for patients with metastatic or unresectable cutaneous melanoma harboring a BRAF V600 mutation, such as BRAF V600K (NCCN.org). detail...
BRAF V600K skin melanoma sensitive Atezolizumab + Cobimetinib + Vemurafenib Guideline Actionable Zelboraf (vemurafenib) plus Cotellic (cobimetinib) in combination with an immune checkpoint inhibitor, such as Tecentriq (atezolizumab), is included in guidelines as second-line or subsequent therapy (category 2A) for patients with metastatic or unresectable cutaneous melanoma harboring a BRAF V600 mutation, such as BRAF V600K (NCCN.org). detail...
BRAF V600K colorectal cancer predicted - sensitive PF-07799933 Preclinical - Biochemical Actionable In a preclinical study, PF-07799933 inhibited Erk phosphorylation in colorectal cancer cells harboring BRAF V600K in culture (PMID: 38691346). 38691346