ClinVar Genomic variation as it relates to human health

Variant summary: BRIP1 c.254C>T (p.Ser85Leu) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.254C>T has been reported in the literature in individuals affected with breast cancer and colorectal cancer without strong evidence for causality (examples: deVoer_2016 and Easton_2016) . These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This missense variant replaces serine with leucine at codon 85 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 reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26921362, 31822495) and colorectal cancer (PMID: 26901136). This variant has been identified in 3/251440 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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 85 of the BRIP1 protein (p.Ser85Leu). This variant is present in population databases (rs587781830, gnomAD 0.003%). This missense change has been observed in individual(s) with breast, ovarian and colorectal cancer (PMID: 26901136, 26921362, 31822495). ClinVar contains an entry for this variant (Variation ID: 141545). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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.S85L variant (also known as c.254C>T), located in coding exon 3 of the BRIP1 gene, results from a C to T substitution at nucleotide position 254. The serine at codon 85 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in an individual with early onset of familial colorectal cancer (de Voer RM et al. PLoS Genet., 2016 Feb;12:e1005880). This amino acid position is 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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with personal and/or family history of breast and other cancers (PMID: 26901136, 26921362, 31822495, 34326862); This variant is associated with the following publications: (PMID: 26901136, 26921362, 31822495, 34326862)

BRIP1: PM2, BP4