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

被引：375

作者：

Thompson, Bryony A. ^{[1
,2
]}

Spurdle, Amanda B. ^{[1
]}

Plazzer, John-Paul ^{[3
]}

Greenblatt, Marc S. ^{[4
]}

Akagi, Kiwamu ^{[5
]}

Al-Mulla, Fahd ^{[6
]}

Bapat, Bharati ^{[7
]}

Bernstein, Inge ^{[8
,9
]}

Capella, Gabriel ^{[10
]}

den Dunnen, Johan T. ^{[11
]}

du Sart, Desiree ^{[12
]}

Fabre, Aurelie ^{[13
]}

Farrell, Michael P. ^{[14
]}

Farrington, Susan M. ^{[15
]}

Frayling, Ian M. ^{[16
]}

Frebourg, Thierry ^{[17
,18
]}

Goldgar, David E. ^{[19
,20
]}

Heinen, Christopher D. ^{[21
,22
]}

Holinski-Feder, Elke ^{[23
,24
]}

Kohonen-Corish, Maija ^{[25
,26
,27
]}

Robinson, Kristina Lagerstedt ^{[28
]}

Leung, Suet Yi ^{[29
]}

Martins, Alexandra ^{[17
]}

Moller, Pal ^{[30
]}

Morak, Monika ^{[23
,24
]}

Nystrom, Minna ^{[31
]}

Peltomaki, Paivi ^{[32
]}

Pineda, Marta ^{[10
]}

Qi, Ming ^{[33
,34
]}

Ramesar, Rajkumar ^{[35
]}

Rasmussen, Lene Juel ^{[36
]}

Royer-Pokora, Brigitte ^{[37
]}

Scott, Rodney J. ^{[38
,39
]}

Sijmons, Rolf ^{[40
]}

Tavtigian, Sean V. ^{[20
]}

Tops, Carli M. ^{[11
]}

Weber, Thomas ^{[41
]}

Wijnen, Juul ^{[11
]}

Woods, Michael O. ^{[42
]}

Macrae, Finlay ^{[3
]}

Genuardi, Maurizio ^{[43
,44
]}

机构：

[1] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[2] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[3] Royal Melbourne Hosp, Dept Colorectal Med & Genet, Melbourne, Vic, Australia

[4] Univ Vermont, Coll Med, Vermont Canc Ctr, Burlington, VT USA

[5] Saitama Canc Ctr, Div Mol Diag & Canc Prevent, Saitama, Japan

[6] Kuwait Univ, Hlth Sci Ctr, Fac Med, Dept Pathol, Safat, Kuwait

[7] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[8] Danish Hereditary Nonpolyposis Colorectal Canc Re, Copenhagen, Denmark

[9] Aalborg Univ Hosp, Dept Surg Gastroenterol, Aalborg, Denmark

[10] Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain

[11] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands

[12] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Mol Genet Lab, Melbourne, Vic, Australia

[13] INSERM, Dept Med Genet & Funct Genom, UMR S910, F-13258 Marseille, France

[14] Mater Private Hosp, Dept Canc Genet, Dublin, Ireland

[15] Univ Edinburgh, Inst Genet & Mol Med, Colon Canc Genet Grp, Edinburgh, Midlothian, Scotland

[16] Univ Wales Hosp, Inst Med Genet, Cardiff CF4 4XN, S Glam, Wales

[17] Univ Rouen, Inst Res & Innovat Biomed, INSERM, U1079, Rouen, France

[18] Rouen Univ Hosp, Dept Genet, Rouen, France

[19] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA

[20] Huntsman Canc Inst, Salt Lake City, UT USA

[21] Univ Connecticut, Ctr Hlth, Ctr Mol Med, Farmington, CT USA

[22] Univ Connecticut, Ctr Hlth, Neag Comprehens Canc Ctr, Farmington, CT USA

[23] Med Genet Zentrum, Munich, Germany

[24] Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany

[25] Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia

[26] Univ Western Sydney, Sch Med, Sydney, NSW, Australia

[27] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW, Australia

[28] Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[29] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Hereditary Gastrointestinal Canc Genet Diag Lab, Pokfulam, Hong Kong, Peoples R China

[30] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Med Genet, Res Grp Inherited Canc, Oslo, Norway

[31] Univ Helsinki, Dept Biosci, Div Genet, Helsinki, Finland

[32] Univ Helsinki, Haartman Inst, Dept Med Genet, Helsinki, Finland

[33] Zhejiang Univ, Sch Med, Affiliated Hosp 1, James Watson Inst Genom Sci,Beijing Genome Inst,C, Beijing, Peoples R China

[34] Univ Rochester, Med Ctr, Sch Med & Dent, Rochester, NY 14642 USA

[35] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Div Human Genet,MRC,Human Genet Res Unit, ZA-7925 Cape Town, South Africa

[36] Univ Copenhagen, Ctr Healthy Aging, Copenhagen, Denmark

[37] Univ Dusseldorf, Inst Human Genet, Dusseldorf, Germany

[38] Univ Newcastle, Hunter Med Res Inst, Fac Hlth, Discipline Med Genet, Newcastle, NSW 2300, Australia

[39] John Hunter Hosp, Hunter Area Pathol Serv, Div Mol Med, Newcastle, NSW, Australia

[40] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[41] State Univ New York Downstate, Dept Surg, Brooklyn, NY USA

[42] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF, Canada

[43] Univ Florence, Dept Biomed Expt & Clin Sci, Florence, Italy

[44] Fiorgen Fdn Pharmacogen, Florence, Italy

来源：

NATURE GENETICS | 2014年 / 46卷 / 02期

基金：

英国医学研究理事会; 欧洲研究理事会; 美国国家卫生研究院;

关键词：

NONPOLYPOSIS COLORECTAL-CANCER; UNKNOWN CLINICAL-SIGNIFICANCE; MSH6 GERMLINE MUTATIONS; HUMAN GENOME VARIATION; LYNCH-SYNDROME; SEQUENCE VARIANTS; MICROSATELLITE INSTABILITY; COLON-CANCER; MISSENSE SUBSTITUTIONS; TUMOR CHARACTERISTICS;

D O I：

10.1038/ng.2854

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页码：107 / +

页数：11

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