Evaluating the molecular diagnostic yield of joint genotyping-based approach for detecting rare germline pathogenic and putative loss-of-function variants.

Purpose: Cohort-based germline variant characterization is the standard approach for pathogenic variant discovery in clinical and research samples. However, the impact of cohort size on the molecular diagnostic yield of joint genotyping is largely unknown.

Methods: Head-to-head comparison of the molecular diagnostic yield of joint genotyping in two cohorts of 239 cancer patients in the absence and then in the presence of 100 additional germline exomes.

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.

Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.

Inherited DNA-Repair Defects in Colorectal Cancer.

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown.