rs149016505

Description

The p.V1060I variant (also known as c.3178G>A), located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3178. The valine at codon 1060 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in patients with breast cancer (Tung N et al. Cancer. 2015 Jan;121:25-33; Easton DF et al. J. Med. Genet. 2016 05;53:298-309). This amino acid position is poorly 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.

This missense variant replaces valine with isoleucine at codon 1060 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26921362). This variant has also been identified in 2/251440 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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1060 of the BRIP1 protein (p.Val1060Ile). This variant is present in population databases (rs149016505, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 461140). 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.

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Easton 2016); This variant is associated with the following publications: (PMID: 26921362)