ClinVar

Description

Variant summary: BRCA2 c.8825C>T (p.Ala2942Val) results in a non-conservative amino acid change located in the Nucleic acid-binding, OB-fold domain (IPR012340) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250828 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8825C>T has been reported in the literature in individuals affected with colorectal cancer, breast cancer or acute myeloid leukemia (examples: Peariman_2019, Kwong_2020, Nie_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been reported (MSH6 c.2194C>T, p.R732X), providing supporting evidence for a benign role (Peariman_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32068069, 34741701, 30877237, 34250417). ClinVar contains an entry for this variant (Variation ID: 141807). Based on the evidence outlined above, the variant was classified as uncertain significance.