BRIP1 (BRCA1 interacting protein) is a DNA repair gene that contributes to the DNA repair function of BRCA1. BRIP1 has been linked to familial ovarian cancer and hereditary breast cancer (autosomal dominant), and Fanconi anemia complementation group J (autosomal recessive). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split the autosomal recessive Fanconi anemia complementation group J into separate curation due to phenotypic variability and different inheritance patterns. We also curated separately the autosomal dominant hereditary breast cancer to refute the gene-disease relationship. Therefore, this curation solely focuses on autosomal dominant familial ovarian cancer. This gene-disease relationship has been studied in at least six case-control or cohort studies at the aggregate variant level (12 points). Five case-control studies suggested significant increased risk for ovarian cancer in monoallelic BRIP1 variant carriers compared to controls (PMIDs: 26315354, 26720728, 29368626, 32359370, 35172496). Another case-control study (PMID: 31341520) showed conflicting results, in which the authors found a significant association of pathogenic variants in BRIP1 and ovarian cancer by analyzing crude data; whereas age-adjusted data showed no ovarian cancer association, which may reflect that BRIP1 variant carriers are more likely to be diagnosed with late-onset ovarian cancer than non-carriers. This gene-disease relationship is also supported by experimental evidence of protein interaction assay and cell culture models (1.5 Points; PMIDs: 11301010, 14576433, 16153896). Pull-down and co-immunoprecipitation assays revealed that the BRCT domain of BRCA1 protein directly interacts with phosphorylated BRIP1, which is further required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Cells deficient of BRIP1 also failed to elicit homologous recombination after DNA double stranded breaks. In summary, BRIP1 is definitively associated with autosomal dominant familial ovarian cancer. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated as definitive by the Breast/Ovarian Cancer GCEP on 10/12/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 07/28/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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