Abstract: Methods and materials are described for determining the susceptibility of an individual to diseases associated with defects in DNA mismatch repair function, principally human colorectal and other cancers, by the use of activity assays to assess the functional significance of mutations in genes encoding DNA mismatch repair proteins. These methods allow the prospective identification of amino acid substitutions, corresponding to naturally occurring genetic mutations, which impair human DNA mismatch repair function and may lead to oncogenic consequences. Certain irregular sequences encoding protein sequences that differ from native DNA mismatch repair proteins, and which may foretell a higher probability for developing cancer and other genetically based diseases, have been now been newly identified by these methods.