Inherited mutations in the MSH2 and MLH1 homologs of the bacterial DNA mismatch repair genes MutS and MutL were initially demonstrated at high frequency in HNPCC and were shown to be associated with microsatellite instability. The demonstration that 10-45% of pancreatic, gastric, breast, ovarian and small cell lung cancers also display microsatellite instability has been interpreted to sμggest that DNA mismatch repair is not restricted to HNPCC tumors but is a common feature in tumor initiation or progression. Two additional homologs of the prokaryotic MutL gene, designated PMS1 and PMS2, have been identified and shown to be mutated in the germline of HNPCC patients.