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 journalReview articlepeer-review

294 Scopus citations


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 languageEnglish (US)
Pages (from-to)107-115
Number of pages9
JournalNature Genetics
Issue number2
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Genetics


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