ClinVar

Description

Variant summary: BRIP1 c.2564G>A (p.Arg855His) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal (IPR006555) of 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 6.3e-05 in 268654 control chromosomes. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. The variant, c.2564G>A, has been reported in the literature in individuals affected with LS, pancreatic, breast, and colon cancer (Yurgelun_2015, Dudley_2018, Easton_2016, Schubert_2019) but also in healthy controls (Ramus_2015). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 26315354, 29360161, 30426508, 26921362). ClinVar contains an entry for this variant (Variation ID: 128175). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.