Association of high and moderate penetrance monogenic variants, polygenic risk, and family history with breast cancer in an ancestrally diverse population

Abstract

Limited data are available on genomic risk factors for breast cancer in diverse populations. We evaluated breast cancer risk conferred by high and moderate penetrance genes, polygenic risk scores (PRS), and family history (FH) in an ancestrally diverse biobank. We identified expected pathogenic variants (EPVs) in 14 genes among 30,223 sequenced individuals, including 15,919 unrelated women. Using electronic health records (EHRs), we evaluated associations of EPVs and PRS with breast cancer, stratified by FH and relative to individuals without EPVs and without FH. EPVs in high penetrance genes were associated with increased risk of breast cancer both without FH (OR 6.8, p = 1.4 × 10-10) or with FH (OR 11.8, p = 4.1 × 10-21). EPVs in moderate penetrance genes were associated with increased risk only among individuals with FH (OR 7.0, p = 4.7 × 10-10 with FH; OR 1.2, p = 0.6 without FH). High PRS (≥ 90th percentile) was associated with increased risk (OR 1.8, p = 3.3 × 10-8) and low PRS (≤ 10th percentile) with reduced risk (OR 0.6, p = 1.6 × 10-3) of breast cancer. FH further modified risk across PRS strata. EHR review of 252 women with EPVs in moderate penetrance genes revealed that 75 (29.8%) met criteria for clinical genetic testing, and only 27 (36.0%) had undergone testing. High and moderate penetrance genes and PRS confer varying degrees of breast cancer risk, with FH modifying these associations. There is a need to better identify women with moderate penetrance gene variants.