title: Nine novel pathogenic germline mutations in MLH1, MSH2, MSH6 and PMS2 in families with Lynch syndrome.
abstract: Many germline mutations in the DNA mismatch repair genes have been described so far leading to the clinical phenotype of Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC). Most mutations are private mutations. We report on nine novel pathogenic germline mutations that have been found in families meeting either the Amsterdam or the Bethesda criteria. These findings include the mutations MLH1,c.884+4A>G, MLH1,c.1377_1378insA;p.Glu460ArgfsX19, MLH1,c.1415_1416delGA;p.Arg472ThrfsX5, MSH2,c.301G>T;p.Glu101X, MSH2,c.638_639delTG;p.Leu213GlnfsX18, MSH2,c.842C>A;p.Ser281X, MSH2,c.859G>T;p.Gly287X, MSH6,c.2503C>T;p.Gln835X and a large genomic deletion of exons 1-10 of the PMS2 gene. The mutation MLH1,c.884+4A>G detected in two families results in a complete skipping of exon 10 on mRNA level and thus has been considered as pathogenic. In all cases the tumor tissue of the index patient revealed high microsatellite instability (MSI-H) and showed a complete loss of expression of the affected protein in the tumor cells by immunohistochemistry (IHC). The findings underline the importance of a pre-screening of tumor tissue for an efficient definition of conspicuous cases.
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany. rahner@uni-bonn.de
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Maria
authors.initials: M
authors.lastname: Wehner
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Waltraut
authors.initials: W
authors.lastname: Friedl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Constanze
authors.initials: C
authors.lastname: Walldorf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016021:Epidemiologic Studies; D018095:Germ-Line Mutation; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007150:Immunohistochemistry; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes