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 M., 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, Genuardi, Maurizio, on behalf of InSiGHT and Ward, Robyn (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: 107-115. doi:10.1038/ng.2854

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Author 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 M.
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
Genuardi, Maurizio
on behalf of InSiGHT
Ward, Robyn
Title Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/ng.2854
Volume 46
Issue 2
Start page 107
End page 115
Total pages 11
Place of publication New York, United States
Publisher Nature
Language eng
Formatted 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.
Keyword Nonpolyposis colorectal cancer
Unknown clinical significance
Human genome variation
Lynch syndrome
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 144 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 150 times in Scopus Article | Citations
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