ClinVar

Description

Variant summary: BRCA2 c.9872C>G (p.Ser3291Cys) 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 8.8e-05 in 251200 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.9872C>G has been reported in the literature in settings of multigene panel testing among a cohort of triple-negative breast cancer cohort unselected for family history of breast cancer (example, Couch_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on protein function (example, Ikegami_2020, Mesman_2018). The most pronounced variant effect results in 81% of normal homology directed repair (HDR) activity in a mouse embryonic stem cell (mESC)-based functional assay. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3; Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.