Polygenic scores in Familial breast cancer cases with and without pathogenic variants and the risk of contralateral breast cancer.

Background: Polygenic risk scores (PRS) are not yet standard in clinical risk assessments for familial breast cancer in Sweden. This study evaluated the distribution and impact of an established PRS (PRS₃₁₃) in women undergoing clinical sequencing for hereditary breast cancer.

Findings: We integrated PRS₃₁₃ into a hereditary breast cancer gene panel used in clinical practice and calculated scores for 262 women. Comparisons were made between women with unilateral and contralateral breast cancer, as well as those with and without pathogenic variants in breast cancer susceptibility genes. PRS₃₁₃ was significantly higher in women with contralateral breast cancer (median + 1.3 SD, n = 33, P = 8e-9) compared to those with unilateral disease (median + 0.66 SD, n = 197, P = 5e-10). Elevated PRS₃₁₃ was also observed in women with pathogenic variants, including those in high-penetrance genes (+ 0.65 SD) and moderate-penetrance genes (+ 0.93 SD), compared to population controls. Incorporating PRS₃₁₃ into a clinical risk model (BOADICEA), shifted 20%-27% of women with moderate-penetrance variants and 23%-32% of women without pathogenic variants into different risk categories according to NCCN and NICE guidelines.

Conclusions: Women with familial breast cancer showed elevated PRS₃₁₃, including those with pathogenic variants, contributing to the observed high risk in these families. Integrating PRS into risk assessment and genetic counselling has the potential to refine risk predictions, even among women with breast cancer attributed to monogenic variants.