Missense changes constitute approximately 1/3 and 1/5 of all rare sequence constitutional variations identified in the MLH1 and MSH2 genes by mutation screening. They represent a challenge for the clinician and for the genetic counselor, who often cannot use them for the management of Lynch syndrome families. Several parameters can be evaluated to gain insight into the significance of such unclassified variants (UVs). These include analysis of microsatellite instability (MSI), immunohistochemistry of mismatch repair (MMR) proteins, segregation data, frequency of the variants in control samples, presence of other pathogenic mutations, and functional and mRNA analyses. While none of these variables can be used alone to predict the significance of UVs in a single case, combined evaluation can lead to clinically useful conclusions. This review reports available information on a sample of MLH1 and MSH2 missense UVs, for which MSI and immunohistochemical data could be retrieved from the literature. Currently, since MSI analysis is routinely performed as a diagnostic test for Lynch syndrome, tumor MSI status represents the most important factor for determining the pathogenicity of UVs in MMR genes.