ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2493-1G>A (rs786203451)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478650 SCV000564814 pathogenic not provided 2014-11-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRIP1 c.2493-1G>A or IVS17-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 17 of the BRIP1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. The presence of a BRIP1 mutation may confer an increased risk for female breast cancer and ovarian cancer based on currently available data (Seal 2006, Rafnar 2011, Pennington 2014). In one case-control study, truncating BRIP1 mutations were identified in 9 out of 1,212 individuals previously diagnosed with breast cancer, from BRCA-negative families, and in 2 out of 2,081 controls, suggesting an increased risk for breast cancer (OR = 2.0) (Seal 2006). Of note, BRIP1 missense variants found in this study were not associated with cancer risk. A specific frameshift variant found in an Icelandic cohort was associated with an increased risk for both ovarian and pancreatic cancer, while another frameshift variant, found in a Spanish cohort, conferred an increased risk for both breast and ovarian cancer in a study looking at sequence variants and their association with these cancer types (Rafnar 2011). Pennington et al. (2014) also identified a germline BRIP1 mutation in 4 out of 367 patients, unselected for family history, who had a personal history of ovarian cancer, peritoneal cancer or fallopian tube cancer. Of note, it has been hypothesized that BRIP1 may be a low penetrance allele as families with multiple cases of breast cancer, found to harbor a BRIP1 mutation, have shown incomplete segregation with disease (Seal 2006).Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one in each copy of the gene) mutations in the BRIP1 gene (Seal 2006). This condition is characterized physical abnormalities, bone marrow failure, an increased risk for malignancy in children including leukemia and certain solid tumors. The Fanconi Anemia phenotype due to BRIP1 mutations is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 variants (Apostolou 2013). If a BRIP1 mutation carrier'spartner also carries a BRIP1mutation, the risk to have a child with FA is 25% with each pregnancy.
Invitae RCV000694142 SCV000822573 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-05-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the BRIP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 418096). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.