We conducted the largest investigation of predisposition 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 deletions 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
evidences involving case-control frequency, loss of heterozygosity, expression effect,
and co-localization with mutations and modified residues. Our integrative approach
links rare predisposition variants to functional consequences, informing future guidelines
of variant classification and germline genetic testing in cancer.