ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.92C>G (p.Ala31Gly) (rs397516906)

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Total submissions: 4
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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.
GeneDx RCV000037963 SCV000207745 likely benign not specified 2013-12-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000521017 SCV000659081 uncertain significance Rasopathy 2017-04-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 31 of the BRAF protein (p.Ala31Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. While this variant is not present in population databases (rs397516906), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a BRAF-related disease. 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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