BARD1 was discovered as a binding partner to BRCA1 in 1996 (Wu et al., PMID: 8944023) and was first reported in relation to hereditary breast cancer in 1998 (Thai et al., PMID: 9425226). BARD1-related cancer predisposition is characterized by a susceptibility to breast cancer with emerging evidence suggesting the association of other cancer types including neuroblastoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, breast cancer and neuroblastoma have been lumped into this curation. Please note, autosomal dominant familial ovarian cancer (MONDO:0016248) has been curated separately due to conflicting evidence. The mechanism of pathogenicity is loss of function in which BRCA1 binding is disrupted and subsequent loss of DNA damage response. 6 predicted null variants (nonsense and frameshift) and 2 missense variants reported in 8 probands with breast cancer in 5 publications (PMIDs: 2550351, 31371347, 21344236, 23334666, 28726808) are included in this curation. Several case-control studies further support the association of breast cancer (PMIDs: 15342711, 28418444, 28649662, 31036035, 33471991, 35172496). Additionally, a case-control study supports the association of neuroblastoma (PMIDs: 37688579, 37688570, 36747619). More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays and animal models (2.5 Points, PMIDs: 18443292, 30925164, 33623049). Cells models with BARD1 variants showed impaired DNA damage in line with the proposed mechanism. In addition, both mammary gland conditional knockout Bard1 mice and a BARD1 variant xenograft model showed development of a breast cancer-like mammary tumor. In summary, there is definitive evidence supporting the relationship between BARD1 and autosomal dominant inherited BARD1-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 hereditary breast cancer (MONDO:0016419) by the Breast/Ovarian Cancer GCEP on 08/09/2017. 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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