rs772709195

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1099 of the BRIP1 protein (p.Leu1099Arg). This variant is present in population databases (rs772709195, gnomAD 0.006%). 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: 186266). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 BRIP1 p.L1099R variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs772709195) and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Color, and Quest Diagnostics). The variant was identified in control databases in 2 of 250866 chromosomes at a frequency of     0.000007972, and was observed only in the Latino population in 2 of 34588 chromosomes (freq: 0.00005782) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.L1099 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The p.L1099R variant (also known as c.3296T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3296. The leucine at codon 1099 is replaced by arginine, 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.