ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8342A>T (p.Asn2781Ile) (rs1434821822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000637364 SCV000758820 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 2781 of the BRCA2 protein (p.Asn2781Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 18559594). This variant is also known as 8570A>T in the literature. 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. 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.
Color Health, Inc RCV000772450 SCV000905628 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772450 SCV001178682 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-25 criteria provided, single submitter clinical testing The p.N2781I variant (also known as c.8342A>T), located in coding exon 18 of the BRCA2 gene, results from an A to T substitution at nucleotide position 8342. The asparagine at codon 2781 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in an individual with ovarian cancer (Soegaard M et al. Clin. Cancer Res. 2008 Jun;14:3761-7). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med. 2019 01;21:71-80). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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