title: First report of a de novo germline mutation in the MLH1 gene.
abstract: Hereditary non-polyposis colorectal carcinoma (HNPCC) is an autosomal dominant disorder associated with colorectal and endometrial cancer and a range of other tumor types. Germline mutations in the DNA mismatch repair (MMR) genes, particularly MLH1, MSH2, and MSH6, underlie this disorder. The vast majority of these HNPCC-associated mutations have been proven, or assumed, given the family history of cancer, to be transmitted through several generations. To the best of our knowledge, only a single case of a de novo germline MMR gene mutation (in MSH2) has been reported till now. Here, we report a patient with a de novo mutation in MLH1. We identified a MLH1 Q701X truncating mutation in the blood lymphocytes of a male who had been diagnosed with rectal cancer at the age of 35. His family history of cancer was negative for the first- and second-degree relatives. The mutation could not be detected in the patient' parents and sibling and paternity was confirmed with a set of highly polymorphic markers. Non-penetrance and small family size is the common explanation of verified negative family histories of cancer in patients with a germline MMR gene mutation. However, in addition to some cases explained by non-paternity, de novo germline mutations should be considered as a possible explanation as well. As guidelines that stress not to restrict MMR gene mutation testing to patients with a positive family history are more widely introduced, more cases of de novo MMR gene germline mutations may be revealed.
authors.affiliation: Department of Clinical Genetics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. r.p.stulp@medgen.umcg.nl
authors.forename: Rein P
authors.initials: RP
authors.lastname: Stulp
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.forename: Bart
authors.initials: B
authors.lastname: Mol
authors.forename: Arend
authors.initials: A
authors.lastname: Karrenbeld
authors.forename: Monique
authors.initials: M
authors.lastname: de Raad
authors.forename: Huub J C
authors.initials: HJ
authors.lastname: van der Mijle
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1