ClinVar

Description

Variant summary: BRCA2 c.229A>G (p.Thr77Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.229A>G has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome (Lee_2008, Manie_2016, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported in the BIC database (Study ID 40821-presumably a whole gene deletion reported as BRCA1 943ins10, Stop275) and at our laboratory (BRCA1 c.5251C>T, p.Arg1751X), providing supporting evidence for a benign role. At least two publications provide experimental evidence evaluating an impact on protein function and report that this variant abolishes the Plk1 mediated phosphorylation of BRCA2 at residue Thr77, resulting in failure of BRCA2 localization to the Flemming body and incomplete cytokinesis, suggesting that this mutation may underlie the development of breast cancer (Yata_2014, Takaoka_2014). However, the implications of these observations on the established mechanisms of carcinogenesis are not clearly established. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.