MLH1 and colorectal carcinoma: There were an additional eight tumors from seven VUS carriers that were not reclassified by ACMG/InSiGHT framework, but demonstrated a second hit (Table 3), including ID_176 who carried the MLH1 c.1594G > C p.(Gly532Arg) variant and developed MLH1/PMS2 deficient CRC and EC, in the absence of MLH1 methylation, where a second hit was observed in both tumors.