Mutation carrier probabilities in families with members that have two or more mutations or families with mutations in more than one gene

The current versions of the BOADICEA Model (v5) and the Ovarian Cancer Model (v1) implemented in CanRisk do not allow for the possibility of an individual carrying a pathogenic variant in more than one gene. The models assume a dominant model with the order of precedence being: BRCA1, BRCA2, PALB2, CHEK2 and ATM for the BOADICEA Model; and BRCA1, BRCA2, RAD51D, RAD51C and BRIP1 for the Ovarian Cancer Model. In the presence of a mutation in one gene, no additional risk is conferred by a second mutation in another gene lower in the dominance chain. Therefore, the second observed mutation is ignored. For more details see Lee et al Genet In Med 2016. Please note that under this model, when a family member (other than the proband) carries more than one mutation, or if two or more mutations segregate in a family, the mutation carrier probabilities for the proband may be inaccurate for the genes lower in the dominance chain. For example, when a mother carries  BRCA1 and CHEK2 mutations, the CHEK2 mutation is ignored and the carrier probability for CHEK2 may be inaccurate for the proband.