APC and Constitutional mismatch repair deficiency syndrome: We sought to discriminate whether the underlying reason for the multiplicity of colorectal tumors in case LS-298 and two other similar cases (Figure 1) was due to 1) metastatic disease or nonradical removal of initial lesions; 2) mutagenic stressors, e.g. colibactin; 3) modifying germline variants resulting in ultrahypermutability; or 4) somatic mosaicism, e.g. potential constitutional mismatch repair deficiency syndrome (CMMRD) or involvement of APC that might have escaped detection.