rs779860140

Description

This missense variant replaces serine with alanine at codon 1117 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has also been identified in 6/250850 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1117 of the BRIP1 protein (p.Ser1117Ala). This variant is present in population databases (rs779860140, gnomAD 0.01%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 185199). 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.S1117A variant (also known as c.3349T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3349. The serine at codon 1117 is replaced by alanine, an amino acid with similar properties. This alteration was detected in a cohort of 381 unselected endometrial cancer patients, who underwent multi-gene panel testing (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). 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.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with endometrial cancer (Ring 2016); This variant is associated with the following publications: (PMID: 27443514)

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].