Jongmans MCJ, Zhang J, Kuiper RP, et al. - Through whole-exome sequencing (WES) together with hereditary cancer-associated gene (HCG) analyses, a genetic diagnosis could be achieved in at least 19% of patients diagnosed with colorectal cancer (CRC) at age 25 years or younger without pathogenic variants in the mismatch repair (MMR) genes or APC.

• Persons with CRC at age 25 years or younger without germline pathogenic variants in MMR genes or APC were asked to undergo germline WES (n=23 patients, and 14 patient-parent trios) to explore the occurrence of inherited and/or de novo predisposing variants.

• Experts identified pathogenic variants in other HCGs at a high percentage (19%, n = 7).

• A TP53 variant in 2 patients and a homozygous pathogenic splice site variant in BLM in one other patient was detected, and two heterozygous pathogenic variants in recessive HCGs, MUTYH and MSH3, were revealed.

• One CRC patient carried a germline frameshift variant in POLD1 and an in-trans somatic missense variant impacting the exonuclease domain.

• This suggests the likely contribution of loss-of-function POLE and POLD1 variants, next to missense variants in the exonuclease domain, to an elevated CRC susceptibility.

• Most genes in which de novo variants were found are suggested to be intolerant to loss-of-function variants.

• For the first time, it was described that individuals with CRC diagnosed at age 25 years or younger have potentially pathogenic de novo variants in genes previously not related to cancer that are well-conserved in pathways recognized to be implicated in cancer development.