Abstract
The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early‐onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5′ noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.‐287C>T and PAX5 binding to BRCA2:c.‐296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Highlights
Genetic susceptibility to breast cancer (BC) is complex
The 5′ noncoding regions of BRCA1 and BRCA2 in early onset or familial BC patients with no known BRCA1 or BRCA2 germline pathogenic variant were sequenced at nine different sites as part of an approved ENIGMA project
Theses variants have been submitted to the LOVD databases, www.lovd.nl/BRCA1 and www.lovd.nl/BRCA2
Summary
Multiple germline variants have been identified over the past 25 years that are broadly categorized as high, moderate, and low risk. There is evidence that some alleles confer a moderate risk of cancer. Low-risk variants, largely identified by genome-wide association studies, are usually common and cause subtle functional effects, such as small but significant changes in gene expression due to altered activity of proximal and distal regulatory elements (reviewed in Bogdanova, Helbig, & Dork, 2013; Ghoussaini, Pharoah, & Easton, 2013; Skol, Sasaki, & Onel, 2016). Evidence suggests that combinations of low, moderate, and high-risk variants could confer a clinically significant risk of disease (Ding et al, 2012; Kuchenbaecker et al, 2017; Sawyer et al, 2012). Identification and evaluation of all such variants is crucial for accurately predicting BC risk
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