title: An intronic polymorphism of the hMLH1 gene contributes toward incomplete genetic testing for HNPCC.
abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is a common hereditary cancer. Genetic testing is complicated by the multiple DNA mismatch repair genes that underlie the disorder. Many suspected HNPCC families have no germ-line mutation identified. We reassessed an unusual family that appeared to have 2 individuals homozygous for a germline mutation within exon 1 of the hMLH1 gene. A few rare individuals with two inherited mutations in one of the mismatch repair genes have been reported and appear to have a distinct clinical appearance. However, there were no clinical features in the family discussed here that were consistent with constitutive lack of hMLH1. Redesigning the intronic primers for exon 1 identified a common polymorphism located within the original intronic primer site. The polymorphism prevented amplification of the wild-type allele, giving the erroneous appearance of homozygous inheritance of the mutated allele. Likewise, common intronic polymorphisms, if located within primer sequences on the chromosome harboring the HNPCC germ-line mutation could restrict amplification to only the wild-type allele, which may contribute significantly to the low success rate of identifying mutations in HNPCC families.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton AB T6G 2H7, Canada. susan.andrew@ualberta.ca
authors.forename: Susan E
authors.initials: SE
authors.lastname: Andrew
authors.forename: Darcy
authors.initials: D
authors.lastname: Whiteside
authors.forename: Carolyn
authors.initials: C
authors.lastname: Buzin
authors.forename: Cheryl
authors.initials: C
authors.lastname: Greenberg
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spriggs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D011110:Polymorphism, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1