The BRCA1 protein plays a role as a tumor suppressor, functioning in different cellular processes, including DNA double-strand breaks (DSBs) repair, transcriptional activation, cell cycle regulation and chromatin remodeling. In 1994, Miki et al. identified BRCA1 gene and the association of breast cancer and ovarian cancer. In 2008, Al-Sukhni et al. further found germline BRCA1 variants are linked to pancreatic 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 BRCA1-related cancer predisposition curation. Please note that association of germline pathogenic or likely pathogenic variants in the BRCA1 with autosomal recessive inherited Fanconi Anemia complementation group S (MONDO:0054748) has been split to another curation due to phenotypic variability and different inheritance patterns. 6 families in the Miki et al (PMID: 7545954) and 4 large case-control studies (PMIDs: 12237281, 29922827, 34471974, 34471991) are included in this curation. The mechanism of pathogenicity is known to be loss-of-function. 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 (5.5 points; PMIDs: 7795653, 8589721, 10198641, 10549283, 11562181). A defective G2-M checkpoint accompanied by extensive chromosomal abnormalities was observed in BRCA1 mutant cells. Overexpression of BRCA1 in breast and ovarian cancer cell lines inhibited cell growth. Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DSBs by homologous recombination. Additionally, The Brca1 conditional knockout mice developed mammary tumors with massive chromosomal abnormalities. In summary, BRCA1 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 for breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450) as definitive by the Breast/Ovarian Cancer GCEP on 09/13/2017. This re-curation as Definitive was approved by the ClinGen Hereditary Cancer GCEP on 08/25/2023 (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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