title: Actionable exomic incidental findings in 6503 participants: challenges of variant classification.
abstract: Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Laura M
authors: LM
authors: Amendola
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Michael O
authors: MO
authors: Dorschner
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Peggy D
authors: PD
authors: Robertson
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Joseph S
authors: JS
authors: Salama
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Ragan
authors: R
authors: Hart
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Brian H
authors: BH
authors: Shirts
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors: Mitzi L
authors: ML
authors: Murray
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Mari J
authors: MJ
authors: Tokita
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Carlos J
authors: CJ
authors: Gallego
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Daniel Seung
authors: DS
authors: Kim
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
authors: James T
authors: JT
authors: Bennett
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: David R
authors: DR
authors: Crosslin
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Jane
authors: J
authors: Ranchalis
authors: Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
authors: Kelly L
authors: KL
authors: Jones
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Elisabeth A
authors: EA
authors: Rosenthal
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Ella R
authors: ER
authors: Jarvik
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Andy
authors: A
authors: Itsara
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Emily H
authors: EH
authors: Turner
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Daniel S
authors: DS
authors: Herman
authors: Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors: Jennifer
authors: J
authors: Schleit
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Amber
authors: A
authors: Burt
authors: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Seema M
authors: SM
authors: Jamal
authors: Department of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
authors: Jenica L
authors: JL
authors: Abrudan
authors: The Framingham Heart Study, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts 01702, USA;
authors: Andrew D
authors: AD
authors: Johnson
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors: Laura K
authors: LK
authors: Conlin
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Department of Pediatrics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
authors: Matthew C
authors: MC
authors: Dulik
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors: Avni
authors: A
authors: Santani
authors: Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
authors: Danielle R
authors: DR
authors: Metterville
authors: Partners Healthcare Personalized Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
authors: Melissa
authors: M
authors: Kelly
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
authors: Ann Katherine M
authors: AK
authors: Foreman
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
authors: Kristy
authors: K
authors: Lee
authors: Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
authors: Kent D
authors: KD
authors: Taylor
authors: Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
authors: Xiuqing
authors: X
authors: Guo
authors: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA;
authors: Kristy
authors: K
authors: Crooks
authors: Department of Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors: Lesli A
authors: LA
authors: Kiedrowski
authors: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA;
authors: Leslie J
authors: LJ
authors: Raffel
authors: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA;
authors: Ora
authors: O
authors: Gordon
authors: Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors: Kalotina
authors: K
authors: Machini
authors: Department of Genetic and Genomic Medicine, Division of Medical Genetics, Mount Sinai Hospital, New York, New York 10029, USA;
authors: Robert J
authors: RJ
authors: Desnick
authors: Genetic Diseases Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA;
authors: Leslie G
authors: LG
authors: Biesecker
authors: Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
authors: Steven A
authors: SA
authors: Lubitz
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
authors: Surabhi
authors: S
authors: Mulchandani
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
authors: Greg M
authors: GM
authors: Cooper
authors: Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors: Steven
authors: S
authors: Joffe
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239, USA;
authors: C Sue
authors: CS
authors: Richards
authors: Department of Pediatrics, Division of Infectious Disease, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
authors: Yaoping
authors: Y
authors: Yang
authors: Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
authors: Jerome I
authors: JI
authors: Rotter
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA;
authors: Stephen S
authors: SS
authors: Rich
authors: The Framingham Heart Study, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts 01702, USA; Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
authors: Jonathan S
authors: JS
authors: Berg
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors: Nancy B
authors: NB
authors: Spinner
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
authors: James P
authors: JP
authors: Evans
authors: Department of Bioethics and Humanities, University of Washington, Seattle, Washington 98195, USA;
authors: Stephanie M
authors: SM
authors: Fullerton
authors: Genetic Services, Group Health Cooperative, Seattle, Washington 98112, USA;
authors: Kathleen A
authors: KA
authors: Leppig
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Robin L
authors: RL
authors: Bennett
authors: Department of Neurology, University of Washington, Seattle, Washington 98195, USA; Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, Washington 98108, USA;
authors: Thomas
authors: T
authors: Bird
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Dermatology, Group Health Cooperative, Seattle, Washington 98112, USA;
authors: Virginia P
authors: VP
authors: Sybert
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington 98195, USA;
authors: William M
authors: WM
authors: Grady
authors: Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA; Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington 98105, USA;
authors: Holly K
authors: HK
authors: Tabor
authors: Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Jerry H
authors: JH
authors: Kim
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
authors: Michael J
authors: MJ
authors: Bamshad
authors: Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, Washington 98105, USA; Department of Pediatrics, Division of Bioethics, University of Washington, Seattle, Washington 98195, USA.
authors: Benjamin
authors: B
authors: Wilfond
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Arno G
authors: AG
authors: Motulsky
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: C Ronald
authors: CR
authors: Scott
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
authors: Colin C
authors: CC
authors: Pritchard
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Tom D
authors: TD
authors: Walsh
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Bioethics and Humanities, University of Washington, Seattle, Washington 98195, USA;
authors: Wylie
authors: W
authors: Burke
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Wendy H
authors: WH
authors: Raskind
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
authors: Peter
authors: P
authors: Byers
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
authors: Fuki M
authors: FM
authors: Hisama
authors: Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors: Heidi
authors: H
authors: Rehm
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Debbie A
authors: DA
authors: Nickerson
authors: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
authors: Gail P
authors: GP
authors: Jarvik
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics; D059472:Exome; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D056726:Genetic Association Studies; D005820:Genetic Testing; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D033162:Incidental Findings; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
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