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

Thompson, Bryony A., Spurdle, Amanda B., Plazzer, John-Paul, Greenblatt, Marc S., Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capella, Gabriel, den Dunnen, Johan T., du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P., Farrington, Susan M., Frayling, Ian, Frebourg, Thierry, Goldgar, David E., Heinen, Christopher D., Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J., Sijmons, Rolf, Tavtigian, Sean V., Tops, Carli M., Weber, Thomas, Wijnen, Juul, Woods, Michael O., Macrae, Finlay and Genuardi, Maurizio 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) , pp. 107-115.

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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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Nature Publishing Group
ISSN:	1061-4036
Last Modified:	12 Mar 2019 14:47
URI:	https://orca.cardiff.ac.uk/id/eprint/70074

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