Combining rare and common genetic variants improves population risk stratification for breast cancer

Purpose This study aimed to evaluate the performance of different genetic screening approaches to identify women at high-risk of breast cancer in the general population. Methods We retrospectively studied 25,591 women with available electronic health records and genetic data, participants in the Healthy Nevada Project. Results Family history of breast cancer was ascertained on or after the record of breast cancer for 78% of women with both, indicating that this risk assessment method is not being properly utilized for early screening. Genetics offered an alternative method for risk assessment. 11.4% of women were identified as high-risk based on possessing a predicted loss-of-function (pLOF) variant in BRCA1, BRCA2 or PALB2 (hazard ratio = 10.4, 95% confidence interval: 8.1-13.5), or a pLOF variant in ATM or CHEK2 (HR = 3.4, CI: 2.4-4.8), or being in the top 10% of the polygenic risk score (PRS) distribution (HR = 2.4, CI: 2.0-2.8). Moreover, women with a pLOF in ATM or CHEK2 and ranking in the top 50% of the PRS displayed a high risk (39.2% probability of breast cancer at age 70), while their counterparts in the bottom 50% of the PRS were not at high risk (14.4% probability at age 70). Conclusion Our findings suggest that a combined monogenic and polygenic approach allowed a better identification of participants with high risk while minimizing false positives.