Mutation of hMLH1, a gene involved in DNA mismatch repair, is responsible for some families carrying the hereditary non-polypotic colorectal cancer (HNPCC) syndrome. To establish a basis for presymptomatic diagnosis of HNPCC patients who carry germline mutations in this gene, we determined the exon—intron organization of hMLH1. The results indicated that hMLH1 consists of 19 coding exons spanning approximately 100 kb, and that exons 1–7 contain a region that is highly conserved in the MLH1 and PMS1 genes of yeast. We used PCR—SSCP analysis and DNA sequencing to examine the entire coding region of the MLH1 gene in DNAs of 34 unrelated cancer patients who belong to HNPCC pedigrees. Germline mutations were detectable in eight (24%) of these patients; four of them were missense mutations, one had occurred in an Intron where it would affect splicing, and the remaining three were frameshift mutations resulting in truncation of the gene product downstream of the mutation site.

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