POLE and brain neoplasm: As these three POLE PVs were so far found only as somatic mutations in ultra-mutated (>50 Mut/Mb) tumors but not as germline variants in PPAP patients, we speculated that they have a stronger “mutator” effect than known PPAP-causing PVs and, therefore, cause a more severe phenotype with CRC and/or brain tumors in childhood and adolescence as well as CMMRD-like non-malignant features [16,17].