rs145859791

Description

This sequence change replaces leucine with glutamine at codon 958 of the BRIP1 protein (p.Leu958Gln). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is present in population databases (rs145859791, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187210). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

The p.L958Q variant (also known as c.2873T>A), located in coding exon 18 of the BRIP1 gene, results from a T to A substitution at nucleotide position 2873. The leucine at codon 958 is replaced by glutamine, an amino acid with dissimilar 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.

Variant summary: The BRIP1 c.2873T>A (p.Leu958Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121090 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). This variant was reported in a cohort of HBOC patients (Yorczyk_Clinical Genetics_2014) and it was classifies as a VUS/unknown by two different laboratories (cited in ClinVar). Taken together, this variant is classified as VUS.