Causes for Frequent Pathogenic Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift.

We have previously demonstrated that the Norwegian frequent pathogenic ) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent variants in fertile ages as a surrogate marker for fitness. We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent variants, and compared our observed results to penetrance of infrequent variants and to average penetrance of variants reported by others. The cumulative risk for breast cancer at 45 years in carriers of frequent variants was 20% (94% confidence interval 10⁻30%), compared to 35% (95% confidence interval 22⁻48%) in carriers of infrequent variants ( = 0.02), and to the 35% (confidence interval 32⁻39%) average for carriers reported by others ( = 0.0001). Carriers of the most frequent Norwegian variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few variants are frequent, the later onset of breast cancer associated with the most frequent variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.