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

Bryony A Thompson; Amanda B Spurdle; John-Paul Plazzer; Marc S Greenblatt; Kiwamu Akagi; Fahd Al-Mulla; Bharati Bapat; Inge Bernstein; Gabriel Capellá; Johan T den Dunnen; Desiree du Sart; Aurelie Fabre; Michael P Farrell; Susan M Farrington; Ian M Frayling; Thierry Frebourg; David E Goldgar; Christopher D Heinen; Elke Holinski-Feder; Maija Kohonen-Corish; Kristina Lagerstedt Robinson; Suet Yi Leung; Alexandra Martins; Pal Moller; Monika Morak; Minna Nystrom; Paivi Peltomaki; Marta Pineda; Ming Qi; Rajkumar Ramesar; Lene Juel Rasmussen; Brigitte Royer-Pokora; Rodney J Scott; Rolf Sijmons; Sean V Tavtigian; Carli M Tops; Thomas Weber; Juul Wijnen; Michael O Woods; Finlay Macrae; Maurizio Genuardi; Adela Castillejo; Adrienne Sexton; Anthony K W Chan; Alessandra Viel; Amie Blanco; Amy French; Andreas Laner; Anja Wagner; Ans van den Ouweland; on behalf of InSiGHT

doi: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

Bryony A Thompson, Amanda B Spurdle, John-Paul Plazzer, Marc S Greenblatt, Kiwamu Akagi, Fahd Al-Mulla, Bharati Bapat, Inge Bernstein, Gabriel Capellá, Johan T den Dunnen, Desiree du Sart, Aurelie Fabre, Michael P Farrell, Susan M Farrington, Ian M Frayling, Thierry Frebourg, David E Goldgar, Christopher D Heinen, Elke Holinski-Feder, Maija Kohonen-CorishKristina Lagerstedt Robinson, Suet Yi Leung, Alexandra Martins, Pal Moller, Monika Morak, Minna Nystrom, Paivi Peltomaki, Marta Pineda, Ming Qi, Rajkumar Ramesar, Lene Juel Rasmussen, Brigitte Royer-Pokora, Rodney J Scott, Rolf Sijmons, Sean V Tavtigian, Carli M Tops, Thomas Weber, Juul Wijnen, Michael O Woods, Finlay Macrae, Maurizio Genuardi, Adela Castillejo, Adrienne Sexton, Anthony K W Chan, Alessandra Viel, Amie Blanco, Amy French, Andreas Laner, Anja Wagner, Ans van den Ouweland, on behalf of InSiGHT

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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.

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	2
Pages (from-to)	107-115
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2854
Publication status	Published - 2014

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Thompson, B. A., Spurdle, A. B., Plazzer, J-P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., Bapat, B., Bernstein, I., Capellá, 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., ... on behalf of InSiGHT (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. https://doi.org/10.1038/ng.2854

@article{9072ce580c28407daddfc7a3c8e96885,

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.",

author = "Thompson, {Bryony A} and Spurdle, {Amanda B} and John-Paul Plazzer and Greenblatt, {Marc S} and Kiwamu Akagi and Fahd Al-Mulla and Bharati Bapat and Inge Bernstein and Gabriel Capell{\'a} and {den Dunnen}, {Johan T} and {du Sart}, Desiree and Aurelie Fabre and Farrell, {Michael P} and Farrington, {Susan M} and Frayling, {Ian M} and Thierry Frebourg and Goldgar, {David E} and Heinen, {Christopher D} and Elke Holinski-Feder and Maija Kohonen-Corish and Robinson, {Kristina Lagerstedt} and Leung, {Suet Yi} and Alexandra Martins and Pal Moller and Monika Morak and Minna Nystrom and Paivi Peltomaki and Marta Pineda and Ming Qi and Rajkumar Ramesar and Rasmussen, {Lene Juel} and Brigitte Royer-Pokora and Scott, {Rodney J} and Rolf Sijmons and Tavtigian, {Sean V} and Tops, {Carli M} and Thomas Weber and Juul Wijnen and Woods, {Michael O} and Finlay Macrae and Maurizio Genuardi and Adela Castillejo and Adrienne Sexton and Chan, {Anthony K W} and Alessandra Viel and Amie Blanco and Amy French and Andreas Laner and Anja Wagner and {van den Ouweland}, Ans and {on behalf of InSiGHT}",

year = "2014",

doi = "10.1038/ng.2854",

language = "English",

volume = "46",

pages = "107--115",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

Thompson, BA, Spurdle, AB, Plazzer, J-P, 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, Castillejo, A, Sexton, A, Chan, AKW, Viel, A, Blanco, A, French, A, Laner, A, Wagner, A, van den Ouweland, A & on behalf of InSiGHT 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, vol. 46, no. 2, pp. 107-115. https://doi.org/10.1038/ng.2854

TY - JOUR

T1 - Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

AU - Thompson, Bryony A

AU - Spurdle, Amanda B

AU - Plazzer, John-Paul

AU - Greenblatt, Marc S

AU - Akagi, Kiwamu

AU - Al-Mulla, Fahd

AU - Bapat, Bharati

AU - Bernstein, Inge

AU - Capellá, Gabriel

AU - den Dunnen, Johan T

AU - du Sart, Desiree

AU - Fabre, Aurelie

AU - Farrell, Michael P

AU - Farrington, Susan M

AU - Frayling, Ian M

AU - Frebourg, Thierry

AU - Goldgar, David E

AU - Heinen, Christopher D

AU - Holinski-Feder, Elke

AU - Kohonen-Corish, Maija

AU - Robinson, Kristina Lagerstedt

AU - Leung, Suet Yi

AU - Martins, Alexandra

AU - Moller, Pal

AU - Morak, Monika

AU - Nystrom, Minna

AU - Peltomaki, Paivi

AU - Pineda, Marta

AU - Qi, Ming

AU - Ramesar, Rajkumar

AU - Rasmussen, Lene Juel

AU - Royer-Pokora, Brigitte

AU - Scott, Rodney J

AU - Sijmons, Rolf

AU - Tavtigian, Sean V

AU - Tops, Carli M

AU - Weber, Thomas

AU - Wijnen, Juul

AU - Woods, Michael O

AU - Macrae, Finlay

AU - Genuardi, Maurizio

AU - Castillejo, Adela

AU - Sexton, Adrienne

AU - Chan, Anthony K W

AU - Viel, Alessandra

AU - Blanco, Amie

AU - French, Amy

AU - Laner, Andreas

AU - Wagner, Anja

AU - van den Ouweland, Ans

AU - on behalf of InSiGHT

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1038/ng.2854

DO - 10.1038/ng.2854

M3 - Journal article

C2 - 24362816

SN - 1061-4036

VL - 46

SP - 107

EP - 115

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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