title: Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization.
abstract: 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 ρ = 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.
authors: Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: K Joeri
authors: KJ
authors: van der Velde
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Joël
authors: J
authors: Kuiper
authors: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Bryony A
authors: BA
authors: Thompson
authors: Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Australia.
authors: John-Paul
authors: JP
authors: Plazzer
authors: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Gert
authors: G
authors: van Valkenhoef
authors: Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Mark
authors: M
authors: de Haan
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Jan D H
authors: JD
authors: Jongbloed
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Cisca
authors: C
authors: Wijmenga
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Tom J
authors: TJ
authors: de Koning
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Kristin M
authors: KM
authors: Abbott
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Richard
authors: R
authors: Sinke
authors: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Amanda B
authors: AB
authors: Spurdle
authors: Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Australia.|Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.
authors: Finlay
authors: F
authors: Macrae
authors: Institute of Medical Genetics, "A. Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors: Maurizio
authors: M
authors: Genuardi
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Rolf H
authors: RH
authors: Sijmons
authors: Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Morris A
authors: MA
authors: Swertz
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019295:Computational Biology; D053843:DNA Mismatch Repair; D056726:Genetic Association Studies; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D012984:Software
keywords: Lynch syndrome; cumulative link model; pathogenicity prediction; variant classification