rs786202927

Description

<span style="font-family:arial,sans-serif; font-size:10pt">The <span style="font-family:arial,sans-serif">p.K1078* variant, (also known as c.3232A>T) located in coding exon 19 of the BRIP1 gene, results from an A to T substitution at nucleotide position 3232. This changes the amino acid <span style="background-color:initial">at codon 1078 <span style="background-color:initial">from a lysine to a stop codon. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 171 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, <span style="font-family:arial,sans-serif; font-size:10pt"><span style="background-color:initial">the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC <span style="font-family:arial,sans-serif">et al. J. Biol<span style="font-family:arial,sans-serif">. Chem<span style="font-family:arial,sans-serif">. 2011 Feb; 286(6):4292-301. Xie J <span style="font-family:arial,sans-serif">et al. PLoS<span style="font-family:arial,sans-serif"> Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. <span style="font-family:arial,sans-serif">Mol. Cell, 2010 Feb;37:438-46).<span style="background-color:initial"> Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change creates a premature translational stop signal (p.Lys1078*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 172 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: 186406). 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.