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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.

Thompson, Bryony A; Spurdle, Amanda B; Plazzer, John-Paul; Greenblatt, Marc S; Akagi, Kiwamu; Al-Mulla, Fahd; Bapat, Bharati; Bernstein, Inge; Capellá, Gabriel and den Dunnen, Johan T, et al. (2014) In Nature Genetics 46. p.107-115
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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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.... (More)
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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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. (Less)
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Nature Genetics
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46
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107 - 115
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Nature Publishing Group
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  • pmid:24362816
  • wos:000331208300006
  • scopus:84895789502
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1546-1718
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10.1038/ng.2854
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English
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ac767d37-23d7-488b-a918-9baf522a16b8 (old id 4223160)
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http://www.ncbi.nlm.nih.gov/pubmed/24362816?dopt=Abstract
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@article{ac767d37-23d7-488b-a918-9baf522a16b8,
  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.},
  author       = {Thompson, Bryony A and Spurdle, Amanda B and Plazzer, John-Paul and Greenblatt, Marc S and Akagi, Kiwamu and Al-Mulla, Fahd and Bapat, Bharati and Bernstein, Inge and Capellá, Gabriel and den Dunnen, Johan T and du Sart, Desiree and Fabre, Aurelie and Farrell, Michael P and Farrington, Susan M and Frayling, Ian M and Frebourg, Thierry and Goldgar, David E and Heinen, Christopher D and Holinski-Feder, Elke and Kohonen-Corish, Maija and Robinson, Kristina Lagerstedt and Leung, Suet Yi and Martins, Alexandra and Moller, Pal and Morak, Monika and Nystrom, Minna and Peltomaki, Paivi and Pineda, Marta and Qi, Ming and Ramesar, Rajkumar and Rasmussen, Lene and Royer-Pokora, Brigitte and Scott, Rodney J and Sijmons, Rolf and Tavtigian, Sean V and Tops, Carli M and Weber, Thomas and Wijnen, Juul and Woods, Michael O and Macrae, Finlay and Genuardi, Maurizio and Castillejo, Adela and Sexton, Adrienne and Chan, Anthony K W and Viel, Alessandra and Blanco, Amie and French, Amy and Laner, Andreas and Wagner, Anja and van den Ouweland, Ans and Mensenkamp, Arjen and Payá, Artemio and Betz, Beate and Redeker, Bert and Smith, Betsy and Espenschied, Carin and Cummings, Carole and Engel, Christoph and Fornes, Claudia and Valenzuela, Cristian and Alenda, Cristina and Buchanan, Daniel and Barana, Daniela and Konstantinova, Darina and Cairns, Dianne and Glaser, Elizabeth and Silva, Felipe and Lalloo, Fiona and Crucianelli, Francesca and Hogervorst, Frans and Casey, Graham and Tomlinson, Ian and Blanco, Ignacio and Villar, Isabel López and Garcia-Planells, Javier and Bigler, Jeanette and Shia, Jinru and Martinez-Lopez, Joaquin and Gille, Johan J P and Hopper, John and Potter, John and Soto, José Luis and Kantelinen, Jukka and Ellis, Kate and Mann, Kirsty and Varesco, Liliana and Zhang, Liying and Le Marchand, Loic and Marafie, Makia J and Nordling, Margareta and Tibiletti, Maria Grazia and Kahan, Mariano Ariel and Ligtenberg, Marjolijn and Clendenning, Mark and Jenkins, Mark and Speevak, Marsha and Digweed, Martin and Kloor, Matthias and Hitchins, Megan and Myers, Megan and Aronson, Melyssa and Dominguez, Mev and Kutsche, Michael and Parsons, Michael and Walsh, Michael and Kansikas, Minttu and Zahary, Mohd Nizam and Pedroni, Monica and Heider, Nao and Poplawski, Nicola and Rahner, Nils and Lindor, Noralane M and Sala, Paola and Nan, Peng and Propping, Peter and Newcomb, Polly and Sarin, Rajiv and Haile, Robert and Hofstra, Robert and Ward, Robyn and Tricarico, Rossella and Bacares, Ruben and Young, Sean and Chialina, Sergio and Kovalenko, Serguei and Gunawardena, Shanaka R and Moreno, Sira and Ho, Siu Lun and Yuen, Siu Tsan and Thibodeau, Stephen N and Gallinger, Steve and Burnett, Terrilea and Teitsch, Therese and Chan, Tsun Leung and Smyrk, Tom and Cranston, Treena and Psofaki, Vasiliki and Steinke-Lange, Verena and Barbera, Victor-Manuel},
  issn         = {1546-1718},
  language     = {eng},
  pages        = {107--115},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.},
  url          = {http://dx.doi.org/10.1038/ng.2854},
  volume       = {46},
  year         = {2014},
}