ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 6453A>C; This variant is associated with the following publications: (PMID: 31131967)

Variant summary: BRCA2 c.6225A>C (p.Lys2075Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249130 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6225A>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Phyllodes tumors (PT), that are rare fibroepithelial breast neoplasms (example, Rosenberger_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR capacity) based on a high throughput cell based viability assay (MANO-B method) to evaluate drug sensitivity of the BRCA2 variants treated with PARP inhibitors (olaparib, niraparib, rucaparib and carboplatin) at various concentrations. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). At-least one submitter reporting a likely benign outcome cites an alternate molecular mechanism of disease in their reported proband. Based on the evidence outlined above, the variant was classified as likely benign.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.