Evidence is accruing that polygenic risk scores have a role in both the general population and carriers of rare, high-risk genetic variants. In disorders as diverse as breast cancer, developmental disorders, and schizophrenia, polygenic risk scores affect penetrance, acting as moderators for high-risk variants or structural variation. This highlights a possible role for PRS within the well-established framework of high-risk genetic testing. For example, the Deciphering Developmental Disorders study showed that in 7000 children with severe neurodevelopmental disorders expected to be monogenic in aetiology, common variation affects the overall risk of severe neurodevelopmental disorders. It explains over 7% of the variance and affects the individual presentation of symptoms [77]. The role of common variation in moderating expressivity was confirmed in a large electronic health record study, where, in addition to the large effect from the rare pathogenic variants, PRSs for height and BMI were associated with clinical outcome [78]. In breast cancer, the absolute risk increase in carriers of BRCA1 and BRCA2 pathogenic variants depends on breast cancer polygenic risk scores, which might influence clinical decision-making [79]. The joint modelling
