ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation as the last 116 amino acids are lost and replaced with 15 incorrect amino acids, disrupting the critical TOPBP1 interaction domain (Gong 2010, Leung 2011); Observed in individuals with a personal history of breast or ovarian cancer (Lewis 2005, Walsh 2010, Easton 2016); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26315354, 20616022, 16280053, 26921362, 29922827, 19763819)

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.

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. The mutant transcript is expected to escape nonsense-mediated decay and expressed as a truncated protein that lacks the last 100 amino acids of the protein. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and acetylation site (p.Lys1249) in the C-terminus, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals with breast or ovarian cancer (PMID: 16280053, 20616022), renal cell carcinoma (PMID: 35441217), and in an unaffected control subject (PMID: 26315354). This variant has been identified in 3/250050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

The c.3401delC variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 3401, causing a translational frameshift with a predicted alternate stop codon (p.P1134Lfs*16). This alteration has been reported in individuals with breast and/or ovarian cancer and well as an individual with renal cell carcinoma (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul;107(28):12629-33; Easton DF et al. J Med Genet, 2016 May;53:298-309; Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). One computational model showed no significant effect on mRNA structure as a result of this variant (Lewis AG et al. Breast Cancer Res. 2005 Oct;7(6):R1005-16). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 100 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.