MSH2 germline VUS is potentially relevant to LS when each of the following criteria is met: The MSH2 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 MSH2 allele is documented; microsatellite instability is identified by PCR or NGS; and IHC shows a compatible staining pattern (Supplementary Table 4, INT2GRATE POSITIVE CRC or EC Codes IV-I to IV-II). Here, MLH1 is linked to colorectal carcinoma.