caa a22 4500 445331259 CHVBK 20180317142738.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s10689-011-9431-4 doi (NATIONALLICENCE)springer-10.1007/s10689-011-9431-4 Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies [Elektronische Daten] [Karin Hardt, Sven Heick, Beate Betz, Timm Goecke, Haniyeh Yazdanparast, Robin Küppers, Kati Servan, Verena Steinke, Nils Rahner, Monika Morak, Elke Holinski-Feder, Christoph Engel, Gabriela Möslein, Hans-Konrad Schackert, Magnus von Knebel Doeberitz, Christian Pox, Johannes Hegemann, Brigitte Royer-Pokora] Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A 14 reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral. Springer Science+Business Media B.V., 2011 HNPCC nationallicence MLH1 nationallicence Missense variants nationallicence Variants of unclassified significance nationallicence Hardt Karin Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Heick Sven Institute of Functional Microbial Genomics, Heinrich Heine University, Duesseldorf, Germany aut Betz Beate Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Goecke Timm Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Yazdanparast Haniyeh Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Küppers Robin Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Servan Kati Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Steinke Verena Institute of Human Genetics, University Hospital Bonn, Bonn, Germany aut Rahner Nils Institute of Human Genetics, University Hospital Bonn, Bonn, Germany aut Morak Monika Center of Medical Genetics, University Hospital of the Ludwig-Maximilians-University Munich and MGZ, Munich, Germany aut Holinski-Feder Elke Center of Medical Genetics, University Hospital of the Ludwig-Maximilians-University Munich and MGZ, Munich, Germany aut Engel Christoph Institute of Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany aut Möslein Gabriela Department of Surgery, HELIOS St. Josefs-Hospital, Bochum, Germany aut Schackert Hans-Konrad Department of Surgical Research, University of Technology Dresden, Dresden, Germany aut von Knebel Doeberitz Magnus Institute of Applied Tumor Biology, University Hospital Heidelberg, Heidelberg, Germany aut Pox Christian Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany aut Hegemann Johannes Institute of Functional Microbial Genomics, Heinrich Heine University, Duesseldorf, Germany aut Royer-Pokora Brigitte Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut Familial Cancer Springer Netherlands 10/2(2011-06-01), 273-284 1389-9600 10:2<273 2011 10 10689 https://doi.org/10.1007/s10689-011-9431-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10689-011-9431-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hardt Karin Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Heick Sven Institute of Functional Microbial Genomics, Heinrich Heine University, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Betz Beate Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Goecke Timm Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Yazdanparast Haniyeh Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Küppers Robin Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Servan Kati Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Steinke Verena Institute of Human Genetics, University Hospital Bonn, Bonn, Germany aut NATIONALLICENCE 700 1- Rahner Nils Institute of Human Genetics, University Hospital Bonn, Bonn, Germany aut NATIONALLICENCE 700 1- Morak Monika Center of Medical Genetics, University Hospital of the Ludwig-Maximilians-University Munich and MGZ, Munich, Germany aut NATIONALLICENCE 700 1- Holinski-Feder Elke Center of Medical Genetics, University Hospital of the Ludwig-Maximilians-University Munich and MGZ, Munich, Germany aut NATIONALLICENCE 700 1- Engel Christoph Institute of Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany aut NATIONALLICENCE 700 1- Möslein Gabriela Department of Surgery, HELIOS St. Josefs-Hospital, Bochum, Germany aut NATIONALLICENCE 700 1- Schackert Hans-Konrad Department of Surgical Research, University of Technology Dresden, Dresden, Germany aut NATIONALLICENCE 700 1- von Knebel Doeberitz Magnus Institute of Applied Tumor Biology, University Hospital Heidelberg, Heidelberg, Germany aut NATIONALLICENCE 700 1- Pox Christian Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany aut NATIONALLICENCE 700 1- Hegemann Johannes Institute of Functional Microbial Genomics, Heinrich Heine University, Duesseldorf, Germany aut NATIONALLICENCE 700 1- Royer-Pokora Brigitte Institute of Human Genetics and Anthropology, Heinrich Heine University and University Hospital Duesseldorf, Postfach 101007, 40001, Duesseldorf, Germany aut NATIONALLICENCE 773 0- Familial Cancer Springer Netherlands 10/2(2011-06-01), 273-284 1389-9600 10:2<273 2011 10 10689 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE 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