ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8456A>T (p.Asp2819Val)

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 RCV000567807 SCV000666063 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-11 criteria provided, single submitter clinical testing The p.D2819V variant (also known as c.8456A>T), located in coding exon 18 of the BRCA2 gene, results from an A to T substitution at nucleotide position 8456. The aspartic acid at codon 2819 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148(2):285-295). This variant has also been reported as non-functional in homology-directed DNA repair (HDR) assays (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468 and 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 RCV001240619 SCV001413584 uncertain significance Hereditary breast ovarian cancer syndrome 2019-10-08 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 2819 of the BRCA2 protein (p.Asp2819Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 481554). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.

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