Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes.

Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS. Power to classify VUS was higher for Chinese than United States pedigrees. The number of affected individuals explained the most variation in LODadj (21-38%). The distance to the furthest affected relative (FAR) from the proband explained 1-7% of the variation for the benign VUS and Lynch associated cancers. Minimum age of onset (MAO) explained 5-13% of the variation in families with pathogenic breast/ovarian cancer variants. Random removal of 50% of the phenotype/genotype data reduced power and the variation in LODadj was best explained by FAR followed by the number of affected individuals and MAO when the founder was only two generations from the proband. Power to classify benign variants was ~2x power to classify pathogenic variants. Affecteds-only analysis resulted in virtually no power to correctly classify benign variants and reduced power to classify pathogenic variants. These results can be used to guide recruitment efforts to classify rare and private VUS.