BackgroundLow-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.MethodsWe 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 riskswithoutandwithPRS₃₁₃.ResultsWomen with BC but no pathogenic variants in hereditary BC genes have a higher PRS₃₁₃compared with population controls (mean+0.78 SD, p<3e-9). Implementing PRS₃₁₃in the clinical risk estimation before their BC diagnosis would have changed the recommended follow-up in 24%–45% of women.ConclusionsOur results show the potential impact of incorporating PRS₃₁₃directly in the clinical genomic investigation of women with familial BC.