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No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study

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DOI

  • Mev Dominguez-Valentin, University of Oslo, European Hereditary Tumour Group (EHTG), Imperial College London
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  • John Paul Plazzer, Imperial College London, Royal Melbourne Hospital
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  • Julian R. Sampson, European Hereditary Tumour Group (EHTG), Cardiff University
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  • Christoph Engel, European Hereditary Tumour Group (EHTG), Leipzig University
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  • Stefan Aretz, University of Bonn
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  • Mark A. Jenkins, Melbourne School of Population and Global Health
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  • Lone Sunde
  • Inge Bernstein, Aalborg University
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  • Gabriel Capella, European Hereditary Tumour Group (EHTG), Imperial College London, University of Barcelona
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  • Francesc Balaguer, University of Barcelona
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  • Finlay Macrae, Imperial College London, Royal Melbourne Hospital
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  • Ingrid M. Winship, University of Melbourne
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  • Huw Thomas, Imperial College London
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  • Dafydd Gareth Evans, Manchester University NHS Foundation Trust
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  • John Burn, European Hereditary Tumour Group (EHTG), Imperial College London, Newcastle University
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  • Marc Greenblatt, University of Vermont
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  • Wouter H. de Vos tot Nederveen Cappel, Isala Clinics
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  • Rolf H. Sijmons, European Hereditary Tumour Group (EHTG), Imperial College London, University of Groningen
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  • Maartje Nielsen, Leiden University
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  • Lucio Bertario, IRCCS Istituto Europeo di Oncologia - Milano
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  • Bernardo Bonanni, IRCCS Istituto Europeo di Oncologia - Milano
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  • Maria Grazia Tibiletti, University of Insubria
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  • Giulia Martina Cavestro, Vita-Salute San Raffaele University
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  • Annika Lindblom, Karolinska Institutet
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  • Adriana Della Valle, Hospital Fuerzas Armadas
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  • Francisco Lopez-Kostner, Universidad de los Andes Chile
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  • Karin Alvarez, Universidad de los Andes Chile
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  • Nathan Gluck, Tel Aviv University
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  • Lior Katz, Sheba Medical Center at Tel Hashomer
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  • Karl Heinimann, University of Basel
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  • Carlos A. Vaccaro, Hospital Italiano de Buenos Aires
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  • Sigve Nakken, University of Oslo
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  • Eivind Hovig, University of Oslo
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  • Kate Green, Manchester University NHS Foundation Trust
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  • Fiona Lalloo, Manchester University NHS Foundation Trust
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  • James Hill, Manchester University NHS Foundation Trust
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  • Hans F.A. Vasen, Leiden University
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  • Claudia Perne, University of Bonn
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  • Reinhard Büttner, University of Cologne
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  • Heike Görgens, Technische Universität Dresden
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  • Elke Holinski-Feder, Imperial College London, Ludwig Maximilian University of Munich, Center for Medical Genetics and Primary Health Care
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  • Monika Morak, Ludwig Maximilian University of Munich, Center for Medical Genetics and Primary Health Care
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  • Stefanie Holzapfel, University of Bonn
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  • Robert Hüneburg, University of Bonn
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  • Magnus von Knebel Doeberitz, Heidelberg University , German Cancer Research Center
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  • Markus Loeffler, Leipzig University
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  • Nils Rahner, Heinrich Heine University Düsseldorf
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  • Jürgen Weitz, Technische Universität Dresden
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  • Verena Steinke-Lange, Ludwig Maximilian University of Munich, Center for Medical Genetics and Primary Health Care
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  • Wolff Schmiegel, Ruhr University Bochum
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  • Deepak Vangala, Ruhr University Bochum
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  • Emma J. Crosbie, Manchester University NHS Foundation Trust, Manchester University
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  • Marta Pineda, University of Barcelona
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  • Matilde Navarro, University of Barcelona
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  • Joan Brunet, University of Barcelona
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  • Leticia Moreira, University of Barcelona
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  • Ariadna Sánchez, University of Barcelona
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  • Miquel Serra-Burriel, University of Barcelona
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  • Miriam Mints, Karolinska Institutet
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  • Revital Kariv, Tel Aviv University
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  • Guy Rosner, Tel Aviv University
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  • Tamara Alejandra Piñero, Hospital Italiano de Buenos Aires
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  • Walter Hernán Pavicic, Hospital Italiano de Buenos Aires
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  • Pablo Kalfayan, Hospital Italiano de Buenos Aires
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  • Sanne W. Ten Broeke, Leiden University
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  • Jukka Pekka Mecklin, European Hereditary Tumour Group (EHTG), Imperial College London, University of Jyväskylä
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  • Kirsi Pylvänäinen, University of Jyväskylä
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  • Laura Renkonen-Sinisalo, University of Helsinki
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  • Anna Lepistö, University of Helsinki
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  • Päivi Peltomäki, University of Helsinki
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  • John L. Hopper, Melbourne School of Population and Global Health
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  • Aung Ko Win, Melbourne School of Population and Global Health
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  • Daniel D. Buchanan, University of Melbourne, Royal Melbourne Hospital
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  • Noralane M. Lindor, Mayo Clinic Scottsdale, AZ
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  • Steven Gallinger, University of Toronto
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  • Loïc Le Marchand, University of Hawaii at Manoa
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  • Polly A. Newcomb, Fred Hutchinson Cancer Research Center
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  • Jane C. Figueiredo, Cedars-Sinai Medical Center
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  • Stephen N. Thibodeau, Mayo Clinic Rochester, MN
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  • Christina Therkildsen, University of Copenhagen
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  • Thomas V.O. Hansen
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  • Lars Lindberg, University of Copenhagen
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  • Einar Andreas Rødland, University of Oslo
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  • Florencia Neffa, Hospital Fuerzas Armadas
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  • Patricia Esperon, Hospital Fuerzas Armadas
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  • Douglas Tjandra, Royal Melbourne Hospital, University of Melbourne
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  • Gabriela Möslein, European Hereditary Tumour Group (EHTG), Imperial College London, Witten/Herdecke University
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  • Toni T. Seppälä, European Hereditary Tumour Group (EHTG), Imperial College London, University of Helsinki, Johns Hopkins University
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  • Pål Møller, University of Oslo, European Hereditary Tumour Group (EHTG), Imperial College London

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Original languageEnglish
Article number2856
JournalJournal of Clinical Medicine
Volume10
Issue13
Number of pages12
ISSN2077-0383
DOIs
Publication statusPublished - Jul 2021

    Research areas

  • Aberrant splicing, Cancer incidence, Lynch syndrome, Missense, MLH1, MSH2, Penetrance, Truncating

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