PMS2 germline VUS is potentially relevant to LS when each of the following criteria are met: The PMS2 VUS is the only germline alteration in MMR genes; no other germline alteration related to LS is present; clinical criteria (i.e. PREMM score or Amsterdam II) are met; somatic MLH1 promoter methylation and/or BRAF p.V600E are absent; somatic inactivation of the second PMS2 allele is documented; microsatellite instability is identified by PCR or NGS; and loss of only PMS2 in tumor nuclei by IHC is present (Supplementary Table 3, INT2GRATE POSITIVE CRC Codes III-I to III-III, and EC Code III-I). Here, MLH1 is linked to neoplasm.