Many individuals with multiple or large colorectal adenomas or early-onset 
colorectal cancer (CRC) have no detectable germline mutations in the known 
cancer predisposition genes. Using whole-genome sequencing, supplemented by 
linkage and association analysis, we identified specific heterozygous POLE or 
POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no 
controls. The variants associated with susceptibility, POLE p.Leu424Val and 
POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated 
with endometrial cancer predisposition. The mutations map to equivalent sites in 
the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are 
predicted to cause a defect in the correction of mispaired bases inserted during 
DNA replication. In agreement with this prediction, the tumors from mutation 
carriers were microsatellite stable but tended to acquire base substitution 
mutations, as confirmed by yeast functional assays. Further analysis of 
published data showed that the recently described group of hypermutant, 
microsatellite-stable CRCs is likely to be caused by somatic POLE mutations 
affecting the exonuclease domain.