Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database Journal Article
| Authors: | Thompson, B. A.; Spurdle, A. B.; Plazzer, J. P.; Greenblatt, M. S.; Akagi, K.; Al-Mulla, F.; Bapat, B.; Bernstein, I.; Capellà, 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.; Kohonen-Corish, M.; Lagerstedt Robinson, K.; Leung, S. Y.; Martins, A.; Möller, P.; Morak, M.; Nystrom, M.; Peltomaki, P.; Pineda, M.; Qi, M.; Ramesar, R.; Rasmussen, R. J.; Royer-Pokora, B.; Scott, R. J.; Sijmons, R.; Tavtigian, S. V.; Tops, C. M.; Weber, T.; Wijnen, J.; Woods, M. O.; Macrae, F.; Genuardi, M.; on behalf of InSiGHT |
| Contributors: | Shia, J.; Bacares, R.; Zhang, L. |
| Article 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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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. © 2014 Nature America, Inc. |
| Keywords: | review; classification; gene locus; genetic variability; genetic variation; data base; gastrointestinal neoplasms; standardization; mismatch repair; dna mismatch repair; familial cancer; nomenclature; disease management; tumor gene; mlh1 gene; hereditary nonpolyposis colorectal cancer; databases, genetic; msh2 gene; msh6 gene; humans; human; priority journal; pms2 gene |
| Journal Title: | Nature Genetics |
| Volume: | 46 |
| Issue: | 2 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-02-01 |
| Start Page: | 107 |
| End Page: | 115 |
| Language: | English |
| DOI: | 10.1038/ng.2854 |
| PUBMED: | 24362816 |
| PROVIDER: | scopus |
| PMCID: | PMC4294709 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):11 -- Export Date: 1 August 2014 -- CODEN: NGENE -- Source: Scopus |
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