ClinVar

Description

Variant summary: BRCA2 c.695A>G (p.Tyr232Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250024 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.695A>G has been reported in the literature as a VUS in settings of multigene panel testing in cohorts of patients with breast cancer (Momozawa_2018), prostate cancer (Wei_2019), Esophageal squamous cell carcinoma (ESCC) (Ko_2020) as well as in unaffected controls (Momozawa_2018). These report(s) 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 observed at our laboratory (BRCA2 c.4552delG , p.Glu1518AsnfsX25), providing supporting evidence for a benign role.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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=3; VUS, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.