Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)

被引：98

作者：

Chao, Elizabeth C. ^{[1
]}

Velasquez, Jonathan L. ^{[1
]}

Witherspoon, Mavee S. L. ^{[1
]}

Rozek, Laura S. ^{[2
]}

Peel, David ^{[1
]}

Ng, Pauline ^{[3
]}

Gruber, Stephen B. ^{[2
]}

Watson, Patrice ^{[4
]}

Rennert, Gad ^{[5
,6
,7
]}

Anton-Culver, Hoda ^{[1
]}

Lynch, Henry ^{[4
]}

Lipkin, Steven M. ^{[1
]}

机构：

[1] Univ Calif Irvine, Canc Genet Clin, Div Hematol Oncol, Genet Epidemiol Res Inst, Irvine, CA 92697 USA

[2] Univ Michigan, Dept Internal Med Epidemiol & Human Genet, Ann Arbor, MI 48109 USA

[3] J Craig Venter Inst Human Genet, Rockville, MD USA

[4] Creighton Univ, Sch Med, Hereditary Canc Inst, Omaha, NE USA

[5] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel

[6] Techn Faculty Med, Haifa, Israel

[7] CHS Natl Canc Control Ctr, Haifa, Israel

来源：

HUMAN MUTATION | 2008年 / 29卷 / 06期

关键词：

Lynch syndrome; colorectal cancer; variants of uncertain significance; cancer genetics; HNPCC; MLH1; MSH;

D O I：

10.1002/humu.20735

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is the most common known genetic syndrome for colorectal cancer (CRC). MLH1/MSH2 mutations underlie approximately 90% of Lynch syndrome families. A total of 24% of these mutations are missense. Interpreting missense variation is extremely challenging. We have therefore developed multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), a bioinformatic algorithm that effectively classifies MLH1/MSH2 deleterious and neutral missense variants. We compiled a large database (n>300) of MLH1/MSH2 missense variants with associated clinical and molecular characteristics. We divided this database into nonoverlapping training and validation sets and tested MAPP-MMR. MAPP-MMR significantly outperformed other missense variant classification algorithms (sensitivity, 94%; specificity, 96%; positive predictive value [PPV] 98%; negative predictive value [NPV], 89%), such as SIFT and PolyPhen. MAPP-MMR is an effective bioinformatic tool for missense variant interpretation that accurately distinguishes MLH1/MSH2 deleterious variants from neutral variants.

引用

页码：852 / 860

页数：9

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