ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2992_2993del (p.Lys998fs) (rs878855151)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227245 SCV000291029 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2016-02-26 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 20 of the BRIP1 mRNA (c.2992_2993delAA), causing a frameshift at codon 998. This creates a premature translational stop signal in the last exon of the BRIP1 mRNA (p.Lys998Glufs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated BRIP1 protein. This variant is not present in population databases (ExAC no frequency). While this particular variant has not been reported in the literature, a similar frameshift variant (c.2992_2995delAAGA) has been reported in an individual with breast cancer (PMID: 18628483). This variant affects the BRCA1-binding domain (residues 888-1063) of BRIP1 protein and therefore is expected to disrupt the protein-protein interaction (PMID: 21345144). In experimental studies, the protein product of the c.2992_2995delAAGA variant resulted in reduced protein stability and impaired BRCA1 interaction (PMID: 18628483). In summary, this is a novel frameshift variant in the last exon of the gene. Although it is not expected to result in nonsense mediated decay, it is expected to disrupt the BRCA1-binding domain of BRIP1 protein. Therefore, it has been classified as Likely Pathogenic.
GeneDx RCV000481580 SCV000567735 pathogenic not provided 2015-08-24 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in BRIP1 is denoted c.2992_2993delAA at the cDNA level and p.Lys998GlufsX3 (K998EfsX3) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACA[AA]GAGA. The deletion causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 998, and creates a premature stop codon at position 3 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.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) in the BRIP1 gene (Seal 2006). This condition is characterized by physical abnormalities, bone marrow failure, and 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.
Genetic Services Laboratory, University of Chicago RCV000502446 SCV000593771 likely pathogenic Breast cancer, early-onset 2016-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563472 SCV000664823 pathogenic Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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