No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
Authors: Dominguez-Valentin Mev , Plazzer John-Paul , Sampson Julian R. , Engel Christoph , Aretz Stefan , Jenkins Mark A. , Sunde Lone , Bernstein Inge , Capella Gabriel , Balaguer Francesc , Macrae Finlay , Winship Ingrid M. , Thomas Huw , Evans Dafydd Gareth , Burn John , Greenblatt Marc , de Vos tot Nederveen Cappel Wouter H. , Sijmons Rolf H. , Nielsen Maartje , Bertario Lucio , Bonanni Bernardo , Tibiletti Maria Grazia , Cavestro Giulia Martina , Lindblom Annika , Valle Adriana Della , Lopez-Kostner Francisco , Alvarez Karin , Gluck Nathan , Katz Lior , Heinimann Karl , Vaccaro Carlos A. , Nakken Sigve , Hovig Eivind , Green Kate , Lalloo Fiona , Hill James , Vasen Hans F. A. , Perne Claudia , Büttner Reinhard , Görgens Heike , Holinski-Feder Elke , Morak Monika , Holzapfel Stefanie , Hüneburg Robert , von Knebel Doeberitz Magnus , Loeffler Markus , Rahner Nils , Weitz Jürgen , Steinke-Lange Verena , Schmiegel Wolff , Vangala Deepak , Crosbie Emma J. , Pineda Marta , Navarro Matilde , Brunet Joan , Moreira Leticia , Sánchez Ariadna , Serra-Burriel Miquel , Mints Miriam , Kariv Revital , Rosner Guy , Piñero Tamara Alejandra , Pavicic Walter Hernán , Kalfayan Pablo , Broeke Sanne W. ten , Mecklin Jukka-Pekka , Pylvänäinen Kirsi , Renkonen-Sinisalo Laura , Lepistö Anna , Peltomäki Päivi , Hopper John L. , Win Aung Ko , Buchanan Daniel D. , Lindor Noralane M. , Gallinger Steven , Marchand Loïc Le , Newcomb Polly A. , Figueiredo Jane C. , Thibodeau Stephen N. , Therkildsen Christina , Hansen Thomas V. O. , Lindberg Lars , Rødland Einar Andreas , Neffa Florencia , Esperon Patricia , Tjandra Douglas , Möslein Gabriela , Seppälä Toni T. , Møller Pål 
Published: June 2021

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.