The current versions of the BOADICEA Model (v6) and the Ovarian Cancer Model (v2) 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, ATM, BARD1, RAD51C and RAD51D for the BOADICEA Model; and BRCA1, BRCA2, RAD51D, RAD51C, BRIP1 and PALB2 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 2022.
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.
Additionally, please note that if the proband tests positive for a mutation in a gene, in cases where they had not been screened/tested for mutations in the other genes, it is assumed that the proband is negative for all other genes that have higher order of precedence. This would happen even if some of the proband's relatives test positive for mutations higher order genes; in those cases, it is advised to run the model with and without the information regarding mutations in the proband, and compare the results.
