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*, InSiGHT

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

373 Citations (Scopus)


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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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
Pages (from-to)107-115
Number of pages9
JournalNature Genetics
Issue number2
Publication statusPublished - Feb 2014
Externally publishedYes


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