ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8456A>G (p.Asp2819Gly)

dbSNP: rs1555287655
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001017821 SCV001178973 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-24 criteria provided, single submitter clinical testing The p.D2819G variant (also known as c.8456A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8456. The aspartic acid at codon 2819 is replaced by glycine, an amino acid with similar properties. This alteration was reported as non-functional in an assay of homology-directed DNA repair activity (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001210612 SCV001382108 uncertain significance Hereditary breast ovarian cancer syndrome 2024-04-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2819 of the BRCA2 protein (p.Asp2819Gly). 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: 822455). 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.

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