Germline mutations in mismatch repair genes are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), the most common hereditary cancer-susceptibility syndrome. We report six novel germline mutations, three in MSH2 and three in MLH1. All but one mutation have been found in families fulfilling the criteria of the Bethesda guidelines; two of them additionally fulfilled the Amsterdam criteria. We identified two nonsense mutations in MSH2 (c.1764T>G [p.Y588X], c.2579C>A [p.S860X]), one duplication of four nucleotides causing premature stop codon (MLH1: c.821_824dupAAGC [p.A275fsX307]), one splice site mutation resulting in skipping of exon 8 from the MLH1 transcript (c.677+3A>G), one duplication of 18 nucleotides leading to duplication of six amino acids in the mismatch-binding domain of MSH2 (c.4_21dup [p.A2_E7dup) and one missense mutation in the PMS2 interaction domain of MLH1 (c.1756G>C [p.A586P]). The three latter mutations were not found in 73, 90 and 94 healthy control individuals, respectively. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IH) revealed complete loss of expression of the affected protein in the tumor cells from the patients with the nonsense, splice-site and missense mutation. The tumor from the patient with the c.821_824dupAAGC mutation showed a reduced, rather than lost, expression of the MLH1-protein.

Copyright 2003 Wiley-Liss, Inc.