Rare high penetrance mutations (such as BRCA1 and BRCA2 for breast cancer), while obviously very important to the families who carry them, are of surprisingly little value in population-level prediction (12,13). BRCA1/2 population screening has an AUC of only 0.52, assuming a mutation frequency of 1% (14), a penetrance of 50% (15) and a breast cancer lifetime risk of 12% (16) (see Supplementary Methods for derivation).
