ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4969A>C (p.Asn1657His)

dbSNP: rs587781599
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165819 SCV000216566 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-23 criteria provided, single submitter clinical testing The p.N1657H variant (also known as c.4969A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 4969. The asparagine at codon 1657 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000474260 SCV000549553 uncertain significance Hereditary breast ovarian cancer syndrome 2024-12-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1657 of the BRCA2 protein (p.Asn1657His). 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: 186255). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 RCV001753563 SCV002005388 uncertain significance not provided 2019-04-17 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
University of Washington Department of Laboratory Medicine, University of Washington RCV000165819 SCV003852244 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).
PreventionGenetics, part of Exact Sciences RCV004535120 SCV004108272 uncertain significance BRCA2-related disorder 2023-06-14 criteria provided, single submitter clinical testing The BRCA2 c.4969A>C variant is predicted to result in the amino acid substitution p.Asn1657His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is reported in ClinVar as uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/186255/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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