Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001020075 | SCV001181506 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-08-01 | criteria provided, single submitter | clinical testing | The c.3358_3359delGA variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 3358 to 3359, causing a translational frameshift with a predicted alternate stop codon (p.D1120Ffs*2). 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 only the last 129 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional studies suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal. 2010 Jan; 3(104):ra3; Xie J et al. PLoS Genet. Jul 2012; 8(7): e1002786). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001860971 | SCV002308210 | likely pathogenic | Familial cancer of breast; Fanconi anemia complementation group J | 2021-02-25 | criteria provided, single submitter | clinical testing | 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 disrupts the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein, which 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). 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. This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 823656). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp1120Phefs*2) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 130 amino acid(s) of the BRIP1 protein. |