ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.1511G>T (p.Gly504Val) (rs121913348)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037914 SCV000061576 pathogenic Non-small cell lung cancer 2011-05-03 criteria provided, single submitter clinical testing Somatic BRAF variants have been identified in up to 3% of cases of lung adenocar cinoma (Davies 2002).
Invitae RCV000033302 SCV000288405 likely pathogenic Rasopathy 2016-01-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 464 of the BRAF protein (p.Gly464Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with cardio-facio-cutaneous syndrome (PMID: 18413255, 18039235, 2102266). ClinVar contains an entry for this variant (Variation ID: 40364). Experimental studies have shown that this missense change disrupts BRAF inhibition, resulting in a constitutively active protein (PMID: 23907581, 19376813, 23680146, 25155755). In summary, this missense change results in a constitutively activity protein and is reported in affected individuals. While this variant is likely to be pathogenic, additional genetic data is needed to prove that conclusively. Therefore, it has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285364 SCV001471782 likely pathogenic none provided 2020-02-28 criteria provided, single submitter clinical testing The BRAF c.1391G>T; p.Gly464Val variant (rs121913348) is reported in the literature in individuals affected with cardio-facio-cutaneous syndrome (Rodriguez-Viciana 2008, Yoon 2007). This variant is reported in ClinVar (Variation ID: 40364), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 464 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show increased kinase activation consistent with a gain of function mechanism (Hollestelle 2007, Wan 2004). Based on available information, this variant is considered to be likely pathogenic. References: Hollestelle A et al. Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res. 2007 Feb;5(2):195-201. Rodriguez-Viciana P and Rauen KA. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. Wan PT et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004 Mar 19;116(6):855-67. Yoon G et al. Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol. 2007 Dec;49(12):894-9.
Database of Curated Mutations (DoCM) RCV000442182 SCV000505048 likely pathogenic Neoplasm 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426199 SCV000505049 likely pathogenic Breast neoplasm 2015-07-14 no assertion criteria provided literature only

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