ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4457T>G (p.Val1486Gly)

dbSNP: rs2072504759
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001218272 SCV001390146 uncertain significance Hereditary breast ovarian cancer syndrome 2024-05-01 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1486 of the BRCA2 protein (p.Val1486Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 947244). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
GeneDx RCV001751411 SCV002006071 uncertain significance not provided 2019-06-10 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
University of Washington Department of Laboratory Medicine, University of Washington RCV003158518 SCV003850525 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Ambry Genetics RCV003158518 SCV004005444 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-16 criteria provided, single submitter clinical testing The p.V1486G variant (also known as c.4457T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 4457. The valine at codon 1486 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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