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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database / Thompson, Ba; Spurdle, Ab; Plazzer, Jp; Greenblatt, Ms; Akagi, K; Al Mulla, F; Bapat, B; Bernstein, I; Capellá, G; den Dunnen, Jt; du Sart, D; Fabre, A; Farrell, Mp; Farrington, Sm; Frayling, Im; Frebourg, T; Goldgar, De; Heinen, Cd; Holinski Feder, E; Kohonen Corish, M; Robinson, Kl; Leung, Sy; Martins, A; Moller, P; Morak, M; Nystrom, M; Peltomaki, P; Pineda, M; Qi, M; Ramesar, R; Rasmussen, Lj; Royer Pokora, B; Scott, Rj; Sijmons, R; Tavtigian, Sv; Tops, Cm; Weber, T; Wijnen, J; Woods, Mo; Macrae, F; Genuardi, M; Pedroni, Monica. - In: NATURE GENETICS. - ISSN 1061-4036. - ELETTRONICO. - 46(2014), pp. 107-115. [10.1038/ng.2854]

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

PEDRONI, Monica
2014

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.
46
107
115
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database / Thompson, Ba; Spurdle, Ab; Plazzer, Jp; Greenblatt, Ms; Akagi, K; Al Mulla, F; Bapat, B; Bernstein, I; Capellá, G; den Dunnen, Jt; du Sart, D; Fabre, A; Farrell, Mp; Farrington, Sm; Frayling, Im; Frebourg, T; Goldgar, De; Heinen, Cd; Holinski Feder, E; Kohonen Corish, M; Robinson, Kl; Leung, Sy; Martins, A; Moller, P; Morak, M; Nystrom, M; Peltomaki, P; Pineda, M; Qi, M; Ramesar, R; Rasmussen, Lj; Royer Pokora, B; Scott, Rj; Sijmons, R; Tavtigian, Sv; Tops, Cm; Weber, T; Wijnen, J; Woods, Mo; Macrae, F; Genuardi, M; Pedroni, Monica. - In: NATURE GENETICS. - ISSN 1061-4036. - ELETTRONICO. - 46(2014), pp. 107-115. [10.1038/ng.2854]
Thompson, Ba; Spurdle, Ab; Plazzer, Jp; Greenblatt, Ms; Akagi, K; Al Mulla, F; Bapat, B; Bernstein, I; Capellá, G; den Dunnen, Jt; du Sart, D; Fabre, A; Farrell, Mp; Farrington, Sm; Frayling, Im; Frebourg, T; Goldgar, De; Heinen, Cd; Holinski Feder, E; Kohonen Corish, M; Robinson, Kl; Leung, Sy; Martins, A; Moller, P; Morak, M; Nystrom, M; Peltomaki, P; Pineda, M; Qi, M; Ramesar, R; Rasmussen, Lj; Royer Pokora, B; Scott, Rj; Sijmons, R; Tavtigian, Sv; Tops, Cm; Weber, T; Wijnen, J; Woods, Mo; Macrae, F; Genuardi, M; Pedroni, Monica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1062794
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