ClinVar

Description

This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. The mutant protein would lack the region (codons 1130-1153) that has been shown to be important for TopBP1 binding in vitro and DNA replication-stress response in ex vivo cell culture (PMID: 20159562, 21127055). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants that occur downstream of this variant are reported as disease-causing in ClinVar (e.g., c.3390_3393del (p.Tyr1131Leufs*18), ClinVar Variation ID: 229712). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.