Abstract
The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.
Highlights
Variants in BRCA1 and BRCA2 account for a plurality of hereditary breast and ovarian cancer (HBOC) cases, and are associated with risks of 50–85% for breast cancer and 15–40% for ovarian cancer [1,2,3,4]
BARD1 is a breast cancer susceptibility gene encoding a protein that primarily interacts with BRCA1 in DNA repair
We tested BARD1 variants for DNA repair function and identified several non-functional variants that were localized in parts of the BARD1 protein not previously associated with DNA repair
Summary
Variants in BRCA1 and BRCA2 account for a plurality of hereditary breast and ovarian cancer (HBOC) cases, and are associated with risks of 50–85% for breast cancer and 15–40% for ovarian cancer [1,2,3,4]. Truncated BARD1 variants have been identified in breast and ovarian cancers [10,11,12] and germline variants in the BARD1 gene are associated with increased cancer risk [13] Still, for both BRCA1 and BARD1, the functional and clinical consequences are often unknown for sequence changes that replace the encoded amino acid residue. A gene panel testing 25 breast cancer-associated genes found 42% of all tests have findings of a VUS in one or more genes, indicating many people have such variants and there is a growing need for their classification [15] Datasets such as the Cancer Genome Atlas (TCGA) gather information on missense variants, but are unable to be used for the accurate prediction of the cancer predisposition of a specific VUS. Previous work in our lab has examined the HDR function of 29 BARD1 variants, focusing on the RING and BRCT domains [21]
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