Gene Variant Detail

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Gene BRAF
Variant N581S
Impact List missense
Protein Effect unknown
Gene Variant Descriptions BRAF N581S lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of N581S is unknown as it has been demonstrated to result in intermediate Braf kinase activity (PMID: 15035987), as well as low Braf kinase activity (PMID: 28783719), and results in Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719), however in another study, demonstrated increased transformation ability in one of two different cell lines compared to wild-type Braf (PMID: 29533785), and has been identified as a secondary resistance mutation (PMID: 32553555).
Associated Drug Resistance Y
Category Variants Paths

BRAF mutant BRAF N581X BRAF N581S

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Transcript NM_004333.5
gDNA chr7:g.140753393T>C
cDNA c.1742A>G
Protein p.N581S
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_001354609.1 chr7:g.140753393T>C c.1742A>G p.N581S RefSeq GRCh38/hg38
XM_005250045 chr7:g.140753393T>C c.1742A>G p.N581S RefSeq GRCh38/hg38
NM_004333 chr7:g.140753393T>C c.1742A>G p.N581S RefSeq GRCh38/hg38
NM_004333.5 chr7:g.140753393T>C c.1742A>G p.N581S RefSeq GRCh38/hg38

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  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
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  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF N581S lung adenocarcinoma predicted - sensitive PF-00477736 + PF3644022 Preclinical - Patient cell culture Actionable In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 combination treatment resulted in significant apoptosis in primary tumor cells isolated from a lung adenocarcinoma patient harboring BRAF N581S in culture (PMID: 26140595). 26140595
BRAF N581S 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, 2 of the non-responding patients harbored BRAF N581S (PMID: 29320312; NCT02091141). 29320312
BRAF N581S 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 3 patients harboring BRAF N581S, and enrollment in this cohort was discontinued (PMID: 31959346; NCT02304809). 31959346
BRAF N581S female reproductive organ cancer no benefit Trametinib Case Reports/Case Series Actionable In a Phase II trial (NCI-MATCH), Mekinist (trametinib) treatment did not demonstrate clinical activity in patients with advanced solid tumors or lymphoma harboring BRAF fusion or non-V600 mutations, resulted in stable disease in a patient with gynecologic cancer harboring BRAF N581S (PMID: 31924734; NCT02465060). 31924734
BRAF N581S lung adenocarcinoma no benefit Trametinib Case Reports/Case Series Actionable In a Phase II trial (NCI-MATCH), Mekinist (trametinib) treatment did not demonstrate clinical activity in patients with advanced solid tumors or lymphoma harboring BRAF fusion or non-V600 mutations, resulted in progressive disease in a patient with lung adenocarcinoma harboring BRAF N581S (PMID: 31924734; NCT02465060). 31924734
BRAF N581S colorectal cancer predicted - sensitive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Case Reports/Case Series Actionable In a clinical case study, the combination of Erbitux (cetuximab) with FOLFIRI as a first-line therapy resulted in a partial response with progression-free survival lasting 16 months in a patient with metastatic colorectal cancer harboring BRAF N581S (PMID: 31515458). 31515458