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

ABSTRACT: 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 dist

SUBMITTER: Rosenthal EA 

PROVIDER: S-EPMC5699967 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature