Forgó E, et al. - Via Sanger sequencing for polymerase ε (POLE) exonuclease domain mutations in exons 9, 11, 13 and 14 and confirmed by next-generation sequencing, 63 consecutive mismatch repair (MMR)-intact colorectal carcinomas (CRC) were assessed in order to recognize the morphological, immunophenotypical and molecular characteristics of POLE-mutated CRCs. In exon 9 (p.P286R) or exon 13 (p.V411L), 4.8% CRC (four MMR-intact primary and one MMR-intact metastasis) harbored POLE mutations in amino acid 286. POLE-mutated CRCs arose in the transverse colon and rectum, were male-predominant, younger and exhibited heightened tumor-infiltrating lymphocytes and immune cells at the tumor-stromal interface. With a marked and sustained response, the patient with metastatic POLE-mutated CRC was placed on PD-1 inhibitor treatment. Data designate that POLE-mutated CRCs have hypermutated phenotypes irrespective MMR-intact status, with mutation burdens greater compared with microsatellite-unstable CRCs. Provided the recent approval for treatment of microsatellite-unstable cancer with immune checkpoint inhibitors, evaluation of POLEstatus may aid to guide therapeutic decisions for hypermutated tumors with intact MMR that would contrarily be missed by routine testing.