Submissions for variant NM_004333.6(BRAF):c.92C>G (p.Ala31Gly)

gnomAD frequency: 0.00006  dbSNP: rs397516906

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000521017	SCV000616390	likely benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.92C>G (p.Ala31Gly) variant in the BRAF gene has been identified in at least 1 individual with clinical features of a RASopathy (PS4 not met; Partners LMM internal data; GTR ID's 21766; SCV000061629.5). However, the p.Ala31Gly variant was observed in at least one healthy adult individual who did not have clinical features of a RASopathy (BS2; Partners LMM and GeneDx internal data; GTR ID's 21766, 26957; SCV000061629.5, SCV000207745.9). Computational prediction tools and conservation analysis suggest that the p.Ala31Gly variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037963	SCV000061629	likely benign	not specified	2014-10-22	criteria provided, single submitter	clinical testing	p.Ala31Gly in exon 1 of BRAF: This variant is not expected to have clinical sign ificance because although it has been identified by our laboratory in 1 Caucasia n child with clinical features of Noonan syndrome, it has been identified in 2 u naffected individuals. In addition, no pathogenic sequence variants in individua ls with Noonan spectrum disorders have been identified to date in this region of BRAF.
GeneDx	RCV001703886	SCV000207745	likely benign	not provided	2021-04-19	criteria provided, single submitter	clinical testing
Invitae	RCV000521017	SCV000659081	uncertain significance	RASopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 31 of the BRAF protein (p.Ala31Gly). This variant is present in population databases (rs397516906, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 44833). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813340	SCV002060477	likely benign	Noonan syndrome and Noonan-related syndrome	2017-05-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371831	SCV002686689	likely benign	Cardiovascular phenotype	2020-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.