rs786201632

Description

Variant summary: BRIP1 c.2885T>C (p.Ile962Thr) 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 4e-06 in 250396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2885T>C has been reported in the literature citing the ClinVar database classification as a VUS (as of May-2019) among a discovery cohort of individuals affected with early onset breast cancer (example, Moyer_2020). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.I962T variant (also known as c.2885T>C), located in coding exon 18 of the BRIP1 gene, results from a T to C substitution at nucleotide position 2885. The isoleucine at codon 962 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.