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|Gene Variant Descriptions||BRAF N581S lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of N581S is unclear 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, N581S demonstrated increased transformation ability in one of two different cell lines as compared to wild-type Braf (PMID: 29533785).|
|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 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||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||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||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|
|APC Q1429fs BRAF N581S ERBB2 L755S||rectum adenocarcinoma||no benefit||Fluorouracil + Leucovorin + Trastuzumab||Case Reports/Case Series||Actionable||In a clinical case study, a rectal adenocarcinoma patient harboring APC Q1429fs, BRAF N581S, and ERBB2 L755S did not respond to Herceptin (trastuzumab) treatment in combination with Fluorouracil and Wellcovorin (leucovorin) (PMID: 27626067).||27626067|