rs747907706

Description

Variant summary: BRIP1 c.3050C>T (p.Pro1017Leu) 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 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3050C>T has been reported in the literature in the settings of multigene panel testing in an individual with epithelial ovarian cancer (example, Ramus_2016) and in unaffected controls as well as individuals affected with breast cancer from a UK cohort (example, Easton_2016). 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. Six 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=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1017 of the BRIP1 protein (p.Pro1017Leu). This variant is present in population databases (rs747907706, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian and/or breast cancer (PMID: 26315354, 26921362). ClinVar contains an entry for this variant (Variation ID: 186283). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant is denoted BRIP1 c.3050C>T at the cDNA level, p.Pro1017Leu (P1017L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was identified in 3/13,213 cases and 2/5,242 controls in a breast cancer case-control study, as well as in at least one individual with ovarian cancer (Ramus 2015, Easton 2016). BRIP1 Pro1017Leu was not observed at a significant frequency in large population cohorts (Lek 2016). BRIP1 Pro1017Leu is located in the BRCA1 binding domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRIP1 Pro1017Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.

In silico models in agreement (benign);Other strong data supporting benign classification