No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Mev Dominguez-Valentin, John-Paul Plazzer, Julian R Sampson, Christoph Engel, Stefan Aretz, Mark A Jenkins, Lone Sunde, Inge Bernstein, Gabriel Capella, Francesc Balaguer, Finlay Macrae, Ingrid M Winship, Huw Thomas, Dafydd Gareth Evans, John Burn, Marc Greenblatt, Wouter H de Vos Tot Nederveen Cappel, Rolf H Sijmons, Maartje Nielsen, Lucio BertarioBernardo Bonanni, Maria Grazia Tibiletti, Giulia Martina Cavestro, Annika Lindblom, Adriana Della Valle, Francisco Lopez-Kostner, Karin Alvarez, Nathan Gluck, Lior Katz, Karl Heinimann, Carlos A Vaccaro, Sigve Nakken, Eivind Hovig, Kate Green, Fiona Lalloo, James Hill, Hans F A Vasen, Claudia Perne, Reinhard Büttner, Heike Görgens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hüneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Jürgen Weitz, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Emma J Crosbie, Marta Pineda, Matilde Navarro, Joan Brunet, Leticia Moreira, Ariadna Sánchez, Miquel Serra-Burriel, Miriam Mints, Revital Kariv, Guy Rosner, Tamara Alejandra Piñero, Walter Hernán Pavicic, Pablo Kalfayan, Sanne W Ten Broeke, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Päivi Peltomäki, John L Hopper, Aung Ko Win, Daniel D Buchanan, Noralane M Lindor, Steven Gallinger, Loïc Le Marchand, Polly A Newcomb, Jane C Figueiredo, Stephen N Thibodeau, Christina Therkildsen, Thomas V O Hansen, Lars Lindberg, Einar Andreas Rødland, Florencia Neffa, Patricia Esperon, Douglas Tjandra, Gabriela Möslein, Toni T Seppälä, Pål Møller

Research output: Contribution to journalArticlepeer-review

Abstract

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
JournalJournal of Clinical Medicine
Volume10
Issue number13
DOIs
Publication statusPublished - Jun 28 2021

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