High and moderate penetrant genes, such as BRCA1, BRCA2, PALB2, CHEK2, and ATM, account for approximately 25% of familial breast cancer risk. 1-4 An additional 18% can be attributed to variants, mostly single nucleotide polymorphisms (SNPs), that are common in the population and carry relatively low cancer risks individually.5 However, when risks from individual SNPs are combined, the resulting polygenic risk score (PRS) can significantly alter the breast cancer risk estimate for women, irrespective of family history. Polygenic risk scores have previously been used to improve stratification of breast cancer risk in unaffected women without pathogenic variants (PVs) in breast cancer susceptibility genes and in unaffected women with PVs in BRCA1 and BRCA2.

In this retrospective case-control study, we evaluated the association of an 86-SNP PRS with breast cancer risk in women who carry PVs in high and moderate penetrant breast cancer susceptibility genes. The study cohort included women of Ashkenazi Jewish and/or White/Non-Hispanic ancestry between the ages of 18-84 years old who underwent clinical hereditary cancer testing with a 25-gene pan-cancer panel from July 2016 to January 2019. 141,160 non-carriers and 9,802 PV carriers of BRCA1, BRCA2, PALB2, CHEK2, and ATM were identified. Patients with PVs in other genes or in multiple breast cancer susceptibility genes were excluded.

The 86-SNP PRS significantly modified breast cancer risk for PV carriers in all five genes. We found a similar risk modification for BRCA1 and BRCA2 compared to previous studies (OR 1.20 and 1.23, respectively).6 However, the most pronounced risk modification was observed in CHEK2 PV carriers (OR 1.49). This effect size is considerably higher than BRCA1 and BRCA2 and equivalent to the effect in non-carriers and the general population.7,8 Additionally, the effect is greatest for CHEK2 PV carriers with the highest and lowest PRS distributions.

Women with PVs in CHEK2 have a lifetime breast cancer risk of 23-48%.9 Further stratification with a PRS can differentiate women between the lower or higher end of this spectrum and those whose lifetime risk may be less than 20%. In our study, the 86-SNP PRS identified 65% of CHEK2 PV carriers with a lifetime breast cancer risk of 20% or greater and 35% with a lifetime breast cancer of less than 20%, the threshold at which United States guidelines recommend annual breast MRI.10 Combined with comprehensive genetic testing and other known clinical risk factors, polygenic risk scores can provide a more patient-specific approach to medical management for breast cancer risk. Future studies of polygenic risk scores in additional ancestries, types of cancers, and cancer susceptibility genes will broaden clinical applicability and impact on personalized healthcare.

This study was published on July 1st, 2020. To read the full publication, click here:


  1. Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M. Genetic susceptibility to breast cancer. Molecular Oncology. 2010;4(3):174-191.
  2. Anglian Breast Cancer Study G. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. British Journal of Cancer. 2000;83(10):1301-1308.
  3. Shuen AY, Foulkes WD. Inherited Mutations in Breast Cancer Genes—Risk and Response. Journal of Mammary Gland Biology and Neoplasia. 2011;16(1):3-15.
  4. Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372(23):2243-2257.
  5. Lilyquist J, Ruddy KJ,Vachon CM, Couch FJ. Common Genetic Variation and Breast Cancer Risk – Past, present, and future. Cancer Epidemiology Biomarkers & Prevention. 2018:cebp.1144.2017.
  6. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416.
  7. Mavaddat N, Pharoah PD, Michailidou K, et al. Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015;107(5).
  8. Hughes E, Tshiaba P, Gallagher S, et al. Development and Validation of a Polygenic Risk Score to Predict Breast Cancer Risk. JCO Precision Oncology. 2020;Accepted.
  9. Myriad myRisk. 2020. CHEK2 Gene. [online] Available at: <https://myriadmyrisk.com/gene-results/?gene=CHEK2&allele=1> [Accessed 28 April 2020].
  10. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer Screening and Diagnosis (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. Accessed April 28, 2020.

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