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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

Lookup NU author(s): Professor Sir John BurnORCiD



© 2021 by the authors. Licensee MDPI, Basel, Switzerland.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.

Publication metadata

Author(s): Dominguez-Valentin M, Plazzer J-P, Sampson JR, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Macrae F, Winship IM, Thomas H, Evans DG, Burn J, Greenblatt M, de Vos tot Nederveen Cappel WH, Sijmons RH, Nielsen M, Bertario L, Bonanni B, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Kostner F, Alvarez K, Gluck N, Katz L, Heinimann K, Vaccaro CA, Nakken S, Hovig E, Green K, Lalloo F, Hill J, Vasen HFA, Perne C, Buttner R, Gorgens H, Holinski-Feder E, Morak M, Holzapfel S, Huneburg R, Doeberitz MVK, Loeffler M, Rahner N, Weitz J, Steinke-Lange V, Schmiegel W, Vangala D, Crosbie EJ, Pineda M, Navarro M, Brunet J, Moreira L, Sanchez A, Serra-Burriel M, Mints M, Kariv R, Rosner G, Pinero TA, Pavicic WH, Kalfayan P, Ten Broeke SW, Mecklin J-P, Pylvanainen K, Renkonen-Sinisalo L, Lepisto A, Peltomaki P, Hopper JL, Win AK, Buchanan DD, Lindor NM, Gallinger S, Marchand LL, Newcomb PA, Figueiredo JC, Thibodeau SN, Therkildsen C, Hansen TVO, Lindberg L, Rodland EA, Neffa F, Esperon P, Tjandra D, Moslein G, Seppala TT, Moller P

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Medicine

Year: 2021

Volume: 10

Issue: 13

Online publication date: 28/06/2021

Acceptance date: 16/06/2021

Date deposited: 14/07/2022

ISSN (electronic): 2077-0383

Publisher: MDPI


DOI: 10.3390/jcm10132856


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