Integrating a Polygenic Risk Score into a clinical setting would impact risk predictions in familial breast cancer

Low-impact genetic variants identified in population-based genetic studies are not routinely measured as part of clinical genetic testing in familial breast cancer (BC). We studied the consequences of integrating an established Polygenic Risk Score (PRS) (BCAC 313, PRS₃₁₃) into clinical sequencing of women with familial BC in Sweden.

We developed an add-on sequencing panel to capture 313 risk variants in addition to the clinical screening of hereditary BC genes. Index patients with no pathogenic variant from 87 families, and 1000 population controls, were included in comparative PRS calculations. Including detailed family history, sequencing results and tumour pathology information, we used BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.6 to estimate contralateral and lifetime risks without and with PRS₃₁₃.

Women with BC but no pathogenic variants in hereditary BC genes have a higher PRS₃₁₃ compared with population controls (mean+0.78 SD, p<3e-9). Implementing PRS₃₁₃ in the clinical risk estimation before their BC diagnosis would have changed the recommended follow-up in 24%-45% of women.

Our results show the potential impact of incorporating PRS₃₁₃ directly in the clinical genomic investigation of women with familial BC.