BRCA2 plays a role as a tumor suppressor in transcriptional and cell cycle regulation, DNA double-strand breaks (DSBs) repair, mitophagy and stabilization of replication fork. In 1995, Wooster et al. (PMID: 8524414) identified BRCA2 gene and the association of breast cancer. Subsequently, the association of ovarian cancer and pancreatic cancer with germline BRCA2 variants was reported (PMID: 7597059, 9140390, 11257103). Emerging evidence also reported an increased risk of tumor formation at other sites including prostate cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, these phenotypes have been lumped into this BRCA2-related cancer predisposition curation (MONDO:0700269). Association of germline pathogenic or likely pathogenic variants in the BRCA2 with autosomal recessive inherited Fanconi Anemia complementation group D1 (MONDO:0011584) has curated separately due to phenotypic variability and different inheritance patterns. The mechanism of pathogenicity is known to be loss-of-function. Three publications in which 6 founder variants from individuals and families with breast cancer and ovarian cancer (PMIDs: 8673092, 8673089 and 9361038) and 6 large case-control studies (PMID: 24728189, 28888541, 29922827, 30900310, 33471974, 33471991) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease association is also supported by experimental evidence (4.5 Points; PMIDs: 9126738, 9774970, 11694875, 15899802). Yeast two-hybrid assay showed that brca2 interacts with Rad51, a DNA-repair protein. Brca2-deficient mice were radiation sensitive. Mice with conditional mutants in Brca2 and/or p53 developed mammary tumors. In summary, BRCA2 is definitively associated with autosomal dominant BRCA2-related cancer predisposition. 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 for breast-ovarian cancer, familial, susceptibility to, 2 (MONDO:0012933) by the Breast/Ovarian Cancer GCEP on 09/13/2017. This re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 01/26/2024 (SOP Version 10).
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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