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 Bertario; Bernardo 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

doi:10.3390/jcm10132856

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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 language	English
Article number	2856
Journal	Journal of Clinical Medicine
Volume	10
Issue number	13
Number of pages	12
ISSN	2077-0383
DOIs	https://doi.org/10.3390/jcm10132856
Publication status	Published - 2021
Externally published	Yes

Keywords

Aberrant splicing
Cancer incidence
Lynch syndrome
Missense
MLH1
MSH2
Penetrance
Truncating

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10.3390/jcm10132856

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Dominguez-Valentin, M., Plazzer, J. P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., ... Møller, P. (2021). No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study. Journal of Clinical Medicine, 10(13), [2856]. https://doi.org/10.3390/jcm10132856

No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2 : A prospective lynch syndrome database study. / 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; Della Valle, Adriana; 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; Doeberitz, Magnus von Knebel; 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; Ten Broeke, Sanne W.; 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.

In: Journal of Clinical Medicine, Vol. 10, No. 13, 2856, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Dominguez-Valentin, M, Plazzer, JP, 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, Büttner, R, Görgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hüneburg, 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, Sánchez, A, Serra-Burriel, M, Mints, M, Kariv, R, Rosner, G, Piñero, TA, Pavicic, WH, Kalfayan, P, Ten Broeke, SW, Mecklin, JP, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, 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, Rødland, EA, Neffa, F, Esperon, P, Tjandra, D, Möslein, G, Seppälä, TT & Møller, P 2021, 'No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study', Journal of Clinical Medicine, vol. 10, no. 13, 2856. https://doi.org/10.3390/jcm10132856

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 ; Della Valle, Adriana ; 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 ; Doeberitz, Magnus von Knebel ; 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 ; Ten Broeke, Sanne W. ; 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. / No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2 : A prospective lynch syndrome database study. In: Journal of Clinical Medicine. 2021 ; Vol. 10, No. 13.

@article{d47274b2e837492bbac5b0e8fa8f9668,

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

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.",

keywords = "Aberrant splicing, Cancer incidence, Lynch syndrome, Missense, MLH1, MSH2, Penetrance, Truncating",

author = "Mev Dominguez-Valentin and Plazzer, {John Paul} and Sampson, {Julian R.} and Christoph Engel and Stefan Aretz and Jenkins, {Mark A.} and Lone Sunde and Inge Bernstein and Gabriel Capella and Francesc Balaguer and Finlay Macrae and Winship, {Ingrid M.} and Huw Thomas and Evans, {Dafydd Gareth} and John Burn and Marc Greenblatt and {de Vos tot Nederveen Cappel}, {Wouter H.} and Sijmons, {Rolf H.} and Maartje Nielsen and Lucio Bertario and Bernardo Bonanni and Tibiletti, {Maria Grazia} and Cavestro, {Giulia Martina} and Annika Lindblom and {Della Valle}, Adriana and Francisco Lopez-Kostner and Karin Alvarez and Nathan Gluck and Lior Katz and Karl Heinimann and Vaccaro, {Carlos A.} and Sigve Nakken and Eivind Hovig and Kate Green and Fiona Lalloo and James Hill and Vasen, {Hans F.A.} and Claudia Perne and Reinhard B{\"u}ttner and Heike G{\"o}rgens and Elke Holinski-Feder and Monika Morak and Stefanie Holzapfel and Robert H{\"u}neburg and Doeberitz, {Magnus von Knebel} and Markus Loeffler and Nils Rahner and J{\"u}rgen Weitz and Verena Steinke-Lange and Wolff Schmiegel and Deepak Vangala and Crosbie, {Emma J.} and Marta Pineda and Matilde Navarro and Joan Brunet and Leticia Moreira and Ariadna S{\'a}nchez and Miquel Serra-Burriel and Miriam Mints and Revital Kariv and Guy Rosner and Pi{\~n}ero, {Tamara Alejandra} and Pavicic, {Walter Hern{\'a}n} and Pablo Kalfayan and {Ten Broeke}, {Sanne W.} and Mecklin, {Jukka Pekka} and Kirsi Pylv{\"a}n{\"a}inen and Laura Renkonen-Sinisalo and Anna Lepist{\"o} and P{\"a}ivi Peltom{\"a}ki and Hopper, {John L.} and Win, {Aung Ko} and Buchanan, {Daniel D.} and Lindor, {Noralane M.} and Steven Gallinger and Marchand, {Lo{\"i}c Le} and Newcomb, {Polly A.} and Figueiredo, {Jane C.} and Thibodeau, {Stephen N.} and Christina Therkildsen and Hansen, {Thomas V.O.} and Lars Lindberg and R{\o}dland, {Einar Andreas} and Florencia Neffa and Patricia Esperon and Douglas Tjandra and Gabriela M{\"o}slein and Sepp{\"a}l{\"a}, {Toni T.} and P{\aa}l M{\o}ller",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

doi = "10.3390/jcm10132856",

language = "English",

volume = "10",

journal = "Journal of Clinical Medicine",

issn = "2077-0383",

publisher = "M D P I AG",

number = "13",

}

TY - JOUR

T1 - No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2

T2 - A prospective lynch syndrome database study

AU - Dominguez-Valentin, Mev

AU - Plazzer, John Paul

AU - Sampson, Julian R.

AU - Engel, Christoph

AU - Aretz, Stefan

AU - Jenkins, Mark A.

AU - Sunde, Lone

AU - Bernstein, Inge

AU - Capella, Gabriel

AU - Balaguer, Francesc

AU - Macrae, Finlay

AU - Winship, Ingrid M.

AU - Thomas, Huw

AU - Evans, Dafydd Gareth

AU - Burn, John

AU - Greenblatt, Marc

AU - de Vos tot Nederveen Cappel, Wouter H.

AU - Sijmons, Rolf H.

AU - Nielsen, Maartje

AU - Bertario, Lucio

AU - Bonanni, Bernardo

AU - Tibiletti, Maria Grazia

AU - Cavestro, Giulia Martina

AU - Lindblom, Annika

AU - Della Valle, Adriana

AU - Lopez-Kostner, Francisco

AU - Alvarez, Karin

AU - Gluck, Nathan

AU - Katz, Lior

AU - Heinimann, Karl

AU - Vaccaro, Carlos A.

AU - Nakken, Sigve

AU - Hovig, Eivind

AU - Green, Kate

AU - Lalloo, Fiona

AU - Hill, James

AU - Vasen, Hans F.A.

AU - Perne, Claudia

AU - Büttner, Reinhard

AU - Görgens, Heike

AU - Holinski-Feder, Elke

AU - Morak, Monika

AU - Holzapfel, Stefanie

AU - Hüneburg, Robert

AU - Doeberitz, Magnus von Knebel

AU - Loeffler, Markus

AU - Rahner, Nils

AU - Weitz, Jürgen

AU - Steinke-Lange, Verena

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Crosbie, Emma J.

AU - Pineda, Marta

AU - Navarro, Matilde

AU - Brunet, Joan

AU - Moreira, Leticia

AU - Sánchez, Ariadna

AU - Serra-Burriel, Miquel

AU - Mints, Miriam

AU - Kariv, Revital

AU - Rosner, Guy

AU - Piñero, Tamara Alejandra

AU - Pavicic, Walter Hernán

AU - Kalfayan, Pablo

AU - Ten Broeke, Sanne W.

AU - Mecklin, Jukka Pekka

AU - Pylvänäinen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Peltomäki, Päivi

AU - Hopper, John L.

AU - Win, Aung Ko

AU - Buchanan, Daniel D.

AU - Lindor, Noralane M.

AU - Gallinger, Steven

AU - Marchand, Loïc Le

AU - Newcomb, Polly A.

AU - Figueiredo, Jane C.

AU - Thibodeau, Stephen N.

AU - Therkildsen, Christina

AU - Hansen, Thomas V.O.

AU - Lindberg, Lars

AU - Rødland, Einar Andreas

AU - Neffa, Florencia

AU - Esperon, Patricia

AU - Tjandra, Douglas

AU - Möslein, Gabriela

AU - Seppälä, Toni T.

AU - Møller, Pål

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Aberrant splicing

KW - Cancer incidence

KW - Lynch syndrome

KW - Missense

KW - MLH1

KW - MSH2

KW - Penetrance

KW - Truncating

U2 - 10.3390/jcm10132856

DO - 10.3390/jcm10132856

M3 - Journal article

C2 - 34203177

AN - SCOPUS:85114073501

VL - 10

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

IS - 13

M1 - 2856

ER -