Pathogenic germline variants in 10,389 adult cancers. Huang et al.

Pathogenic Germline Variants in 10,389 Adult Cancers We conducted the largest investigation of predispo- sition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large dele- tions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evi- dences involving case-control frequency, loss of het- erozygosity, expression effect, and co-localization with mutations and modified residues. Our integra- tive approach links rare predisposition variants to functional consequences, informing future guide- lines of variant classification and germline genetic testing in cancer