Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000803914 | SCV000943802 | pathogenic | Familial cancer of breast; Fanconi anemia complementation group J | 2019-03-03 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 18-20 of the BRIP1 gene. The 5' boundary is likely confined to intron 17. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. This variant has not been reported in the literature in individuals with BRIP1-related disease. This truncation affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein. It is expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role on RPA chromatin loading following DNA replication stress and the subsequent activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). A truncating variant (p.Lys998Glufs*60) that lies downstream of this deletion has been determined to be pathogenic (PMID: 18628483, 26921362). This suggests that deletion of this region of the BRIP1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |