ClinVar

Description

Variant summary: BRCA2 c.3662C>A (p.Ser1221Tyr) 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 250308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3662C>A has been reported as a VUS in the literature in individuals affected with breast cancer or with family history of breast cancer (examples: Kleibova_2019, Meindl_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3700_3704delGTAAA, p.Val1234Glnfs), in at least one individual affected with unilateral female breast cancer (example: Kleiblova_2019), providing supporting evidence for a benign role. 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: 31050813, 11802209). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.