rs1420431000

Description

This sequence change creates a premature translational stop signal (p.Leu1077*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 173 amino acid(s) of the BRIP1 protein. This variant is not present in population databases (gnomAD no frequency). 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: 530304). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.L1077* variant (also known as c.3230T>G), located in coding exon 19 of the BRIP1 gene, results from a T to G substitution at nucleotide position 3230. This changes the amino acid from a leucine to a stop codon within coding exon 19. This stop codon occurs near the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 173 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional analysis suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal, 2010 Jan;3:ra3; Xie J et al. PLoS Genet., 2012 Jul;8:e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic.