Diverse mediators of cancer predisposition uncovered by germline whole genome sequencing of unexplained familial cancers.

Rare germline structural variants inactivating MSH2 and BRCA1; novel candidate genes (TSTD2, BRAT1)

Germline WGS analysis of 2,726 All of Us individuals without known pathogenic variants (1,496 cases across 18 cancer types with family history, 1,230 controls) identified rare structural variants inactivating MSH2 in Lynch phenotype individuals and BRCA1 in breast cancer. Cancer polygenic risk scores were enriched in cases. Exome-wide rare variant analysis nominated 6 predisposition candidate genes, including TSTD2 (thyroid) and BRAT1 (breast). Known genomic factors (rare + polygenic) explain 5–11% of unexplained familial cancers.

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This study illustrates the value of germline WGS for detecting structural variants missed by standard NGS panels (such as large intronic MSH2 deletions). Identification of novel candidate genes (TSTD2, BRAT1) opens avenues for expanding predisposition panels. The limitation: only 5–11% of unexplained familial cancers are resolved, highlighting the complexity of predisposition genomic architecture.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Journal quality: 0/1 · Preprint penalty: -1 → Total: 6/10