As our results suggest, the MSI-H phenotype in 3/11 tumors from MSH6 VUS carriers is more likely to be linked to the MLH1 promoter hypermethylation than MSH6 variations found in the families, and thus, if MLH1 expression is lost in the tumor, its promoter hypermethylation should be assayed before the more challenging and time consuming functional assays. This evidence concerns the gene MSH6 and neoplasm.