MSH6 germline VUS is potentially relevant to LS when each of the following criteria is met: The MSH6 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 MSH6 allele is documented; microsatellite instability is identified by PCR or NGS; and only MSH6 is lost in tumor nuclei by IHC (Supplementary Table 5, INT2GRATE POSITIVE CRC or EC Code V-I). Here, BRAF is linked to neoplasm.