Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization

被引：31

作者：

van der Velde, K. Joeri ^{[1
,2
]}

Kuiper, Joel ^{[2
,3
]}

Thompson, Bryony A. ^{[4
]}

Plazzer, John-Paul ^{[5
]}

van Valkenhoef, Gert ^{[3
]}

de Haan, Mark ^{[1
,2
]}

Jongbloed, Jan D. H. ^{[2
]}

Wijmenga, Cisca ^{[2
]}

de Koning, Tom J. ^{[2
]}

Abbott, Kristin M. ^{[2
]}

Sinke, Richard ^{[2
]}

Spurdle, Amanda B. ^{[4
]}

Macrae, Finlay ^{[5
,6
]}

Genuardi, Maurizio ^{[7
]}

Sijmons, Rolf H. ^{[2
]}

Swertz, Morris A. ^{[1
,2
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands

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

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

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

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

[6] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic 3050, Australia

[7] Univ Cattolica Sacro Cuore, Inst Med Genet, A Gemelli Sch Med, I-00168 Rome, Italy

来源：

HUMAN MUTATION | 2015年 / 36卷 / 07期

关键词：

Lynch syndrome; variant classification; pathogenicity prediction; cumulative link model; SUSCEPTIBILITY; CLASSIFICATION; PATHOGENICITY;

D O I：

10.1002/humu.22798

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Next-generation sequencing in clinical diagnostics is providing valuable genomic variant data, which can be used to support healthcare decisions. In silico tools to predict pathogenicity are crucial to assess such variants and we have evaluated a new tool, Combined Annotation Dependent Depletion (CADD), and its classification of gene variants in Lynch syndrome by using a set of 2,210 DNA mismatch repair gene variants. These had already been classified by experts from InSiGHT's Variant Interpretation Committee. Overall, we found CADD scores do predict pathogenicity (Spearman's = 0.595, P < 0.001). However, we discovered 31 major discrepancies between the InSiGHT classification and the CADD scores; these were explained in favor of the expert classification using population allele frequencies, cosegregation analyses, disease association studies, or a second-tier test. Of 751 variants that could not be clinically classified by InSiGHT, CADD indicated that 47 variants were worth further study to confirm their putative pathogenicity. We demonstrate CADD is valuable in prioritizing variants in clinically relevant genes for further assessment by expert classification teams. Published 2015 Wiley Periodicals, Inc.*

引用

页码：712 / 719

页数：8

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