ClinVar

Description

This sequence change creates a premature translational stop signal (p.Pro1134Leufs*16) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs756853672, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and/or renal cancer and unaffected control individuals (PMID: 16280053, 20616022, 26315354, 26921362, 35441217). ClinVar contains an entry for this variant (Variation ID: 220899). 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.