Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219598 | SCV000276104 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-18 | criteria provided, single submitter | clinical testing | The c.3260dupA variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of A at nucleotide position 3260, causing a translational frameshift with a predicted alternate stop codon (p.N1087Kfs*4). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 163 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). One study detected this mutation in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Mendelics | RCV000709528 | SCV000839353 | likely pathogenic | Fanconi anemia complementation group J | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001203231 | SCV001374384 | likely pathogenic | Familial cancer of breast; Fanconi anemia complementation group J | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asn1087Lysfs*4) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 163 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs771654971, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 232062). 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. |
| Color Diagnostics, |
RCV000219598 | SCV001734650 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-06 | criteria provided, single submitter | clinical testing | This variant inserts 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 truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and an 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). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250902 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. |
| Baylor Genetics | RCV003462485 | SCV004217107 | likely pathogenic | Familial cancer of breast | 2023-05-28 | criteria provided, single submitter | clinical testing |