Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Bryony A. Thompson; Amanda B. Spurdle; John Paul Plazzer; Marc S. Greenblatt; Kiwamu Akagi; Fahd Al-Mulla; Bharati Bapat; Inge Bernstein; Gabriel Capellá; Johan T. Den Dunnen; Desiree Du Sart; Aurelie Fabre; Michael P. Farrell; Susan M. Farrington; Ian M. Frayling; Thierry Frebourg; David E. Goldgar; Christopher D. Heinen; Elke Holinski-Feder; Maija Kohonen-Corish; Kristina Lagerstedt Robinson; Suet Yi Leung; Alexandra Martins; Pal Moller; Monika Morak; Minna Nystrom; Paivi Peltomaki; Marta Pineda; Ming Qi; Rajkumar Ramesar; Lene Juel Rasmussen; Brigitte Royer-Pokora; Rodney J. Scott; Rolf Sijmons; Sean V. Tavtigian; Carli M. Tops; Thomas Weber; Juul Wijnen; Michael O. Woods; Finlay Macrae; Maurizio Genuardi; Adela Castillejo; Adrienne Sexton; Anthony K.W. Chan; Alessandra Viel; Amie Blanco; Amy French; Andreas Laner; Anja Wagner; Ans Van Den Ouweland; Arjen Mensenkamp; Artemio Payá; Beate Betz; Bert Redeker; Betsy Smith; Carin Espenschied; Carole Cummings; Christoph Engel; Claudia Fornes; Cristian Valenzuela; Cristina Alenda; Daniel Buchanan; Daniela Barana; Darina Konstantinova; Dianne Cairns; Elizabeth Glaser; Felipe Silva; Fiona Lalloo; Francesca Crucianelli; Frans Hogervorst; Graham Casey; Ian Tomlinson; Ignacio Blanco; Isabel López Villar; Javier Garcia-Planells; Jeanette Bigler; Jinru Shia; Joaquin Martinez-Lopez; Johan J.P. Gille; John Hopper; John Potter; José Luis Soto; Jukka Kantelinen; Kate Ellis; Kirsty Mann; Liliana Varesco; Liying Zhang; Loic Le Marchand; Makia J. Marafie; Margareta Nordling; Maria Grazia Tibiletti; Mariano Ariel Kahan; Marjolijn Ligtenberg; Mark Clendenning; Mark Jenkins; Marsha Speevak; Martin Digweed; Matthias Kloor; Megan Hitchins; Megan Myers; Melyssa Aronson; Mev Dominguez Valentin; Michael Kutsche; Michael Parsons; Michael Walsh; Minttu Kansikas; Mohd Nizam Zahary; Monica Pedroni; Nao Heider; Nicola Poplawski; Nils Rahner; Noralane M. Lindor; Paola Sala; Peng Nan; Peter Propping; Polly Newcomb; Rajiv Sarin; Robert Haile; Robert Hofstra; Robyn Ward; Rossella Tricarico; Ruben Bacares; Sean Young; Sergio Chialina; Serguei Kovalenko; Shanaka R. Gunawardena; Sira Moreno; Siu Lun Ho; Siu Tsan Yuen; Stephen N. Thibodeau; Steve Gallinger; Terrilea Burnett; Therese Teitsch; Tsun Leung Chan; Tom Smyrk; Treena Cranston; Vasiliki Psofaki; Verena Steinke-Lange; Victor Manuel Barbera

doi:10.1038/ng.2854

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Bryony A. Thompson, Amanda B. Spurdle, John Paul Plazzer, Marc S. Greenblatt, Kiwamu Akagi, Fahd Al-Mulla, Bharati Bapat, Inge Bernstein, Gabriel Capellá, Johan T. Den Dunnen, Desiree Du Sart, Aurelie Fabre, Michael P. Farrell, Susan M. Farrington, Ian M. Frayling, Thierry Frebourg, David E. Goldgar, Christopher D. Heinen, Elke Holinski-Feder, Maija Kohonen-CorishKristina Lagerstedt Robinson, Suet Yi Leung, Alexandra Martins, Pal Moller, Monika Morak, Minna Nystrom, Paivi Peltomaki, Marta Pineda, Ming Qi, Rajkumar Ramesar, Lene Juel Rasmussen, Brigitte Royer-Pokora, Rodney J. Scott, Rolf Sijmons, Sean V. Tavtigian, Carli M. Tops, Thomas Weber, Juul Wijnen, Michael O. Woods, Finlay Macrae, Maurizio Genuardi, Adela Castillejo, Adrienne Sexton, Anthony K.W. Chan, Alessandra Viel, Amie Blanco, Amy French, Andreas Laner, Anja Wagner, Ans Van Den Ouweland, Arjen Mensenkamp, Artemio Payá, Beate Betz, Bert Redeker, Betsy Smith, Carin Espenschied, Carole Cummings, Christoph Engel, Claudia Fornes, Cristian Valenzuela, Cristina Alenda, Daniel Buchanan, Daniela Barana, Darina Konstantinova, Dianne Cairns, Elizabeth Glaser, Felipe Silva, Fiona Lalloo, Francesca Crucianelli, Frans Hogervorst, Graham Casey, Ian Tomlinson, Ignacio Blanco, Isabel López Villar, Javier Garcia-Planells, Jeanette Bigler, Jinru Shia, Joaquin Martinez-Lopez, Johan J.P. Gille, John Hopper, John Potter, José Luis Soto, Jukka Kantelinen, Kate Ellis, Kirsty Mann, Liliana Varesco, Liying Zhang, Loic Le Marchand, Makia J. Marafie, Margareta Nordling, Maria Grazia Tibiletti, Mariano Ariel Kahan, Marjolijn Ligtenberg, Mark Clendenning, Mark Jenkins, Marsha Speevak, Martin Digweed, Matthias Kloor, Megan Hitchins, Megan Myers, Melyssa Aronson, Mev Dominguez Valentin, Michael Kutsche, Michael Parsons, Michael Walsh, Minttu Kansikas, Mohd Nizam Zahary, Monica Pedroni, Nao Heider, Nicola Poplawski, Nils Rahner, Noralane M. Lindor, Paola Sala, Peng Nan, Peter Propping, Polly Newcomb, Rajiv Sarin, Robert Haile, Robert Hofstra, Robyn Ward, Rossella Tricarico, Ruben Bacares, Sean Young, Sergio Chialina, Serguei Kovalenko, Shanaka R. Gunawardena, Sira Moreno, Siu Lun Ho, Siu Tsan Yuen, Stephen N. Thibodeau, Steve Gallinger, Terrilea Burnett, Therese Teitsch, Tsun Leung Chan, Tom Smyrk, Treena Cranston, Vasiliki Psofaki, Verena Steinke-Lange, Victor Manuel Barbera

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

294 Scopus citations

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Original language	English (US)
Pages (from-to)	107-115
Number of pages	9
Journal	Nature Genetics
Volume	46
Issue number	2
DOIs	https://doi.org/10.1038/ng.2854
State	Published - Feb 2014

ASJC Scopus subject areas

Genetics

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10.1038/ng.2854

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Thompson, B. A., Spurdle, A. B., Plazzer, J. P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., Bapat, B., Bernstein, I., Capellá, G., Den Dunnen, J. T., Du Sart, D., Fabre, A., Farrell, M. P., Farrington, S. M., Frayling, I. M., Frebourg, T., Goldgar, D. E., Heinen, C. D., Holinski-Feder, E., ... Barbera, V. M. (2014). Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genetics, 46(2), 107-115. https://doi.org/10.1038/ng.2854

Thompson, BA, Spurdle, AB, Plazzer, JP, Greenblatt, MS, Akagi, K, Al-Mulla, F, Bapat, B, Bernstein, I, Capellá, G, Den Dunnen, JT, Du Sart, D, Fabre, A, Farrell, MP, Farrington, SM, Frayling, IM, Frebourg, T, Goldgar, DE, Heinen, CD, Holinski-Feder, E, Kohonen-Corish, M, Robinson, KL, Leung, SY, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, LJ, Royer-Pokora, B, Scott, RJ, Sijmons, R, Tavtigian, SV, Tops, CM, Weber, T, Wijnen, J, Woods, MO, Macrae, F, Genuardi, M, Castillejo, A, Sexton, A, Chan, AKW, Viel, A, Blanco, A, French, A, Laner, A, Wagner, A, Van Den Ouweland, A, Mensenkamp, A, Payá, A, Betz, B, Redeker, B, Smith, B, Espenschied, C, Cummings, C, Engel, C, Fornes, C, Valenzuela, C, Alenda, C, Buchanan, D, Barana, D, Konstantinova, D, Cairns, D, Glaser, E, Silva, F, Lalloo, F, Crucianelli, F, Hogervorst, F, Casey, G, Tomlinson, I, Blanco, I, Villar, IL, Garcia-Planells, J, Bigler, J, Shia, J, Martinez-Lopez, J, Gille, JJP, Hopper, J, Potter, J, Soto, JL, Kantelinen, J, Ellis, K, Mann, K, Varesco, L, Zhang, L, Marchand, LL, Marafie, MJ, Nordling, M, Tibiletti, MG, Kahan, MA, Ligtenberg, M, Clendenning, M, Jenkins, M, Speevak, M, Digweed, M, Kloor, M, Hitchins, M, Myers, M, Aronson, M, Valentin, MD, Kutsche, M, Parsons, M, Walsh, M, Kansikas, M, Zahary, MN, Pedroni, M, Heider, N, Poplawski, N, Rahner, N, Lindor, NM, Sala, P, Nan, P, Propping, P, Newcomb, P, Sarin, R, Haile, R, Hofstra, R, Ward, R, Tricarico, R, Bacares, R, Young, S, Chialina, S, Kovalenko, S, Gunawardena, SR, Moreno, S, Ho, SL, Yuen, ST, Thibodeau, SN, Gallinger, S, Burnett, T, Teitsch, T, Chan, TL, Smyrk, T, Cranston, T, Psofaki, V, Steinke-Lange, V & Barbera, VM 2014, 'Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database', Nature Genetics, vol. 46, no. 2, pp. 107-115. https://doi.org/10.1038/ng.2854

@article{c0f8c09f1fb24648b8785e4a3da617a9,

title = "Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database",

abstract = "The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.",

author = "Thompson, {Bryony A.} and Spurdle, {Amanda B.} and Plazzer, {John Paul} and Greenblatt, {Marc S.} and Kiwamu Akagi and Fahd Al-Mulla and Bharati Bapat and Inge Bernstein and Gabriel Capell{\'a} and {Den Dunnen}, {Johan T.} and {Du Sart}, Desiree and Aurelie Fabre and Farrell, {Michael P.} and Farrington, {Susan M.} and Frayling, {Ian M.} and Thierry Frebourg and Goldgar, {David E.} and Heinen, {Christopher D.} and Elke Holinski-Feder and Maija Kohonen-Corish and Robinson, {Kristina Lagerstedt} and Leung, {Suet Yi} and Alexandra Martins and Pal Moller and Monika Morak and Minna Nystrom and Paivi Peltomaki and Marta Pineda and Ming Qi and Rajkumar Ramesar and Rasmussen, {Lene Juel} and Brigitte Royer-Pokora and Scott, {Rodney J.} and Rolf Sijmons and Tavtigian, {Sean V.} and Tops, {Carli M.} and Thomas Weber and Juul Wijnen and Woods, {Michael O.} and Finlay Macrae and Maurizio Genuardi and Adela Castillejo and Adrienne Sexton and Chan, {Anthony K.W.} and Alessandra Viel and Amie Blanco and Amy French and Andreas Laner and Anja Wagner and {Van Den Ouweland}, Ans and Arjen Mensenkamp and Artemio Pay{\'a} and Beate Betz and Bert Redeker and Betsy Smith and Carin Espenschied and Carole Cummings and Christoph Engel and Claudia Fornes and Cristian Valenzuela and Cristina Alenda and Daniel Buchanan and Daniela Barana and Darina Konstantinova and Dianne Cairns and Elizabeth Glaser and Felipe Silva and Fiona Lalloo and Francesca Crucianelli and Frans Hogervorst and Graham Casey and Ian Tomlinson and Ignacio Blanco and Villar, {Isabel L{\'o}pez} and Javier Garcia-Planells and Jeanette Bigler and Jinru Shia and Joaquin Martinez-Lopez and Gille, {Johan J.P.} and John Hopper and John Potter and Soto, {Jos{\'e} Luis} and Jukka Kantelinen and Kate Ellis and Kirsty Mann and Liliana Varesco and Liying Zhang and Marchand, {Loic Le} and Marafie, {Makia J.} and Margareta Nordling and Tibiletti, {Maria Grazia} and Kahan, {Mariano Ariel} and Marjolijn Ligtenberg and Mark Clendenning and Mark Jenkins and Marsha Speevak and Martin Digweed and Matthias Kloor and Megan Hitchins and Megan Myers and Melyssa Aronson and Valentin, {Mev Dominguez} and Michael Kutsche and Michael Parsons and Michael Walsh and Minttu Kansikas and Zahary, {Mohd Nizam} and Monica Pedroni and Nao Heider and Nicola Poplawski and Nils Rahner and Lindor, {Noralane M.} and Paola Sala and Peng Nan and Peter Propping and Polly Newcomb and Rajiv Sarin and Robert Haile and Robert Hofstra and Robyn Ward and Rossella Tricarico and Ruben Bacares and Sean Young and Sergio Chialina and Serguei Kovalenko and Gunawardena, {Shanaka R.} and Sira Moreno and Ho, {Siu Lun} and Yuen, {Siu Tsan} and Thibodeau, {Stephen N.} and Steve Gallinger and Terrilea Burnett and Therese Teitsch and Chan, {Tsun Leung} and Tom Smyrk and Treena Cranston and Vasiliki Psofaki and Verena Steinke-Lange and Barbera, {Victor Manuel}",

note = "Funding Information: We thank all submitters of data to the InSiGHT database (retrospective and prospective), the Colon Cancer Family Registry and the German Hereditary Non-polyposis Colorectal Cancer Consortium for their contributions of unpublished data, acknowledged formally through microattribution. We would also like to acknowledge L. Marquart for providing statistical advice and T. O{\textquoteright}Mara for providing advice and assistance with the statistical package R. We are extremely grateful to the Hicks Foundation (Australia) for inaugural support of InSiGHT database curator J.-P.P. Funding for VIC teleconferences was provided by the Cancer Council of Victoria. B.A.T. is supported by a Cancer Council of Queensland PhD scholarship and by a Queensland Institute of Medical Research PhD Top-Up award. A.B.S. is a National Health and Medical Research Council Senior Research Fellow. The work performed by A.B.S. and B.A.T. was additionally supported by Cancer Australia (1010859). M.G. is supported by a grant from the Tuscan Tumor Institute (ITT). J.-P.P. is currently supported by the Royal Melbourne Hospital Foundation. S.V.T., M.S.G., A.B.S., L.J.R. and R.S. are supported by grant 1R01CA164944 from the National Cancer Institute/US National Institutes of Health (NCI/US NIH). G.C. and M.P. were supported by the Ministerio de Ciencia e Innovaci{\'o}n (SAF 12-33636) and by the Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer. A.F. is supported by the French National Cancer Institute and by the Institut National du Cancer (INCa) French MMR Committee. S.M.F. is supported by grants from the Association of International Cancer Research (12-1087) and by the Medical Research Council UK (MR/K018647/1). NHS Wales National Institute for Health and Social Care (NIHSCR) funding was provided to I.M.F. via the Cardiff & Vale University Health Board. D.E.G. is supported by funding from Mayo Specialized Programs of Research Excellence (SPORE) grant P50CA11620106 (principal investigator J. Ingle). C.D.H. is funded by US NIH grant R01 CA115783-02/CA/NCI. E.H.-F. and M.M. are supported by German Cancer Aid (Deutsche Krebshilfe) and by the Wilhelm Sander Foundation. M.K.-C. is funded by Cancer Institute NSW. S.Y.L. is supported by the Hong Kong Cancer Fund. A.M. is supported by the French National Cancer Institute and by the Direction G{\'e}n{\'e}rale de l{\textquoteright}Offre des Soins (INCa/DGOS). The Sigrid Juselius Foundation funds M.N. Funding for P.P. is provided by the European Research Council (FP7-ERC-232635). L.J.R. is funded by Nordea-Fonden. B.R.-P. is supported by German Cancer Aid. M.O.W. was supported by the Canadian Cancer Society Research Institute (grant 18223).",

year = "2014",

month = feb,

doi = "10.1038/ng.2854",

language = "English (US)",

volume = "46",

pages = "107--115",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

AU - Thompson, Bryony A.

AU - Spurdle, Amanda B.

AU - Plazzer, John Paul

AU - Greenblatt, Marc S.

AU - Akagi, Kiwamu

AU - Al-Mulla, Fahd

AU - Bapat, Bharati

AU - Bernstein, Inge

AU - Capellá, Gabriel

AU - Den Dunnen, Johan T.

AU - Du Sart, Desiree

AU - Fabre, Aurelie

AU - Farrell, Michael P.

AU - Farrington, Susan M.

AU - Frayling, Ian M.

AU - Frebourg, Thierry

AU - Goldgar, David E.

AU - Heinen, Christopher D.

AU - Holinski-Feder, Elke

AU - Kohonen-Corish, Maija

AU - Robinson, Kristina Lagerstedt

AU - Leung, Suet Yi

AU - Martins, Alexandra

AU - Moller, Pal

AU - Morak, Monika

AU - Nystrom, Minna

AU - Peltomaki, Paivi

AU - Pineda, Marta

AU - Qi, Ming

AU - Ramesar, Rajkumar

AU - Rasmussen, Lene Juel

AU - Royer-Pokora, Brigitte

AU - Scott, Rodney J.

AU - Sijmons, Rolf

AU - Tavtigian, Sean V.

AU - Tops, Carli M.

AU - Weber, Thomas

AU - Wijnen, Juul

AU - Woods, Michael O.

AU - Macrae, Finlay

AU - Genuardi, Maurizio

AU - Castillejo, Adela

AU - Sexton, Adrienne

AU - Chan, Anthony K.W.

AU - Viel, Alessandra

AU - Blanco, Amie

AU - French, Amy

AU - Laner, Andreas

AU - Wagner, Anja

AU - Van Den Ouweland, Ans

AU - Mensenkamp, Arjen

AU - Payá, Artemio

AU - Betz, Beate

AU - Redeker, Bert

AU - Smith, Betsy

AU - Espenschied, Carin

AU - Cummings, Carole

AU - Engel, Christoph

AU - Fornes, Claudia

AU - Valenzuela, Cristian

AU - Alenda, Cristina

AU - Buchanan, Daniel

AU - Barana, Daniela

AU - Konstantinova, Darina

AU - Cairns, Dianne

AU - Glaser, Elizabeth

AU - Silva, Felipe

AU - Lalloo, Fiona

AU - Crucianelli, Francesca

AU - Hogervorst, Frans

AU - Casey, Graham

AU - Tomlinson, Ian

AU - Blanco, Ignacio

AU - Villar, Isabel López

AU - Garcia-Planells, Javier

AU - Bigler, Jeanette

AU - Shia, Jinru

AU - Martinez-Lopez, Joaquin

AU - Gille, Johan J.P.

AU - Hopper, John

AU - Potter, John

AU - Soto, José Luis

AU - Kantelinen, Jukka

AU - Ellis, Kate

AU - Mann, Kirsty

AU - Varesco, Liliana

AU - Zhang, Liying

AU - Marchand, Loic Le

AU - Marafie, Makia J.

AU - Nordling, Margareta

AU - Tibiletti, Maria Grazia

AU - Kahan, Mariano Ariel

AU - Ligtenberg, Marjolijn

AU - Clendenning, Mark

AU - Jenkins, Mark

AU - Speevak, Marsha

AU - Digweed, Martin

AU - Kloor, Matthias

AU - Hitchins, Megan

AU - Myers, Megan

AU - Aronson, Melyssa

AU - Valentin, Mev Dominguez

AU - Kutsche, Michael

AU - Parsons, Michael

AU - Walsh, Michael

AU - Kansikas, Minttu

AU - Zahary, Mohd Nizam

AU - Pedroni, Monica

AU - Heider, Nao

AU - Poplawski, Nicola

AU - Rahner, Nils

AU - Lindor, Noralane M.

AU - Sala, Paola

AU - Nan, Peng

AU - Propping, Peter

AU - Newcomb, Polly

AU - Sarin, Rajiv

AU - Haile, Robert

AU - Hofstra, Robert

AU - Ward, Robyn

AU - Tricarico, Rossella

AU - Bacares, Ruben

AU - Young, Sean

AU - Chialina, Sergio

AU - Kovalenko, Serguei

AU - Gunawardena, Shanaka R.

AU - Moreno, Sira

AU - Ho, Siu Lun

AU - Yuen, Siu Tsan

AU - Thibodeau, Stephen N.

AU - Gallinger, Steve

AU - Burnett, Terrilea

AU - Teitsch, Therese

AU - Chan, Tsun Leung

AU - Smyrk, Tom

AU - Cranston, Treena

AU - Psofaki, Vasiliki

AU - Steinke-Lange, Verena

AU - Barbera, Victor Manuel

N1 - Funding Information: We thank all submitters of data to the InSiGHT database (retrospective and prospective), the Colon Cancer Family Registry and the German Hereditary Non-polyposis Colorectal Cancer Consortium for their contributions of unpublished data, acknowledged formally through microattribution. We would also like to acknowledge L. Marquart for providing statistical advice and T. O’Mara for providing advice and assistance with the statistical package R. We are extremely grateful to the Hicks Foundation (Australia) for inaugural support of InSiGHT database curator J.-P.P. Funding for VIC teleconferences was provided by the Cancer Council of Victoria. B.A.T. is supported by a Cancer Council of Queensland PhD scholarship and by a Queensland Institute of Medical Research PhD Top-Up award. A.B.S. is a National Health and Medical Research Council Senior Research Fellow. The work performed by A.B.S. and B.A.T. was additionally supported by Cancer Australia (1010859). M.G. is supported by a grant from the Tuscan Tumor Institute (ITT). J.-P.P. is currently supported by the Royal Melbourne Hospital Foundation. S.V.T., M.S.G., A.B.S., L.J.R. and R.S. are supported by grant 1R01CA164944 from the National Cancer Institute/US National Institutes of Health (NCI/US NIH). G.C. and M.P. were supported by the Ministerio de Ciencia e Innovación (SAF 12-33636) and by the Fundación Científica de la Asociación Española Contra el Cáncer. A.F. is supported by the French National Cancer Institute and by the Institut National du Cancer (INCa) French MMR Committee. S.M.F. is supported by grants from the Association of International Cancer Research (12-1087) and by the Medical Research Council UK (MR/K018647/1). NHS Wales National Institute for Health and Social Care (NIHSCR) funding was provided to I.M.F. via the Cardiff & Vale University Health Board. D.E.G. is supported by funding from Mayo Specialized Programs of Research Excellence (SPORE) grant P50CA11620106 (principal investigator J. Ingle). C.D.H. is funded by US NIH grant R01 CA115783-02/CA/NCI. E.H.-F. and M.M. are supported by German Cancer Aid (Deutsche Krebshilfe) and by the Wilhelm Sander Foundation. M.K.-C. is funded by Cancer Institute NSW. S.Y.L. is supported by the Hong Kong Cancer Fund. A.M. is supported by the French National Cancer Institute and by the Direction Générale de l’Offre des Soins (INCa/DGOS). The Sigrid Juselius Foundation funds M.N. Funding for P.P. is provided by the European Research Council (FP7-ERC-232635). L.J.R. is funded by Nordea-Fonden. B.R.-P. is supported by German Cancer Aid. M.O.W. was supported by the Canadian Cancer Society Research Institute (grant 18223).

PY - 2014/2

Y1 - 2014/2

N2 - The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

AB - The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

UR - http://www.scopus.com/inward/record.url?scp=84895789502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895789502&partnerID=8YFLogxK

U2 - 10.1038/ng.2854

DO - 10.1038/ng.2854

M3 - Review article

C2 - 24362816

AN - SCOPUS:84895789502

SN - 1061-4036

VL - 46

SP - 107

EP - 115

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

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