MLH1 germline VUS is potentially relevant to LS when each of the following criteria are met: The MLH1 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 MLH1 allele is documented; microsatellite instability is identified by PCR or NGS; and a compatible IHC staining pattern is present (Table 1, INT2GRATE POSITIVE CRC Codes II-I to II-IV and EC Codes II-I to II-II). The gene discussed is MRC1; the disease is colorectal carcinoma.