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


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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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

Type Journal
ISBN 1546-1718 (Electronic) 1061-4036 (Linking)
Authors Thompson, B. A. ; Spurdle, A. B. ; Plazzer, J. P. ; Greenblatt, M. S. ; Akagi, K. ; Al-Mulla, F. ; Bapat, B. ; Bernstein, I. ; Capella, 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. ; Robinson, K. L. ; Leung, S. Y. ; Martins, A. ; Mol
Responsible Garvan Author (missing name)
Published Date 2014-01-01
Published Volume 46
Published Issue 2
Published Pages 107-15
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version