ClinVar

Description

Variant summary: BRCA2 c.241T>A (p.Phe81Ile) 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 2.4e-05 in 251364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.241T>A has been reported in the literature in individuals affected with various cancers, including prostate cancer (Kote-Jarai_2011, Johansson_2019), breast cancer (Dorling_2021) and cutaneous melanoma (Johansson_2019). The variant was also found at a carrier frequency of 0.0001365 in European American women over the age of 70 without history of cancer (FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, and a minigene splicing assay demonstrated that the variant had no impact splicing (Tubeuf_2020). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.