Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Laura M Amendola¹, Michael O Dorschner², Peggy D Robertson³, Joseph S Salama¹, Ragan Hart¹, Brian H Shirts⁴, Mitzi L Murray⁵, Mari J Tokita¹, Carlos J Gallego¹, Daniel Seung Kim⁶, James T Bennett⁷, David R Crosslin⁶, Jane Ranchalis¹, Kelly L Jones⁸, Elisabeth A Rosenthal¹, Ella R Jarvik¹, Andy Itsara¹, Emily H Turner⁹, Daniel S Herman⁴, Jennifer Schleit¹⁰, Amber Burt¹, Seema M Jamal¹¹, Jenica L Abrudan¹², Andrew D Johnson¹³, Laura K Conlin¹⁴, Matthew C Dulik¹⁵, Avni Santani¹⁴, Danielle R Metterville¹⁶, Melissa Kelly¹⁷, Ann Katherine M Foreman¹⁸, Kristy Lee¹⁸, Kent D Taylor¹⁹, Xiuqing Guo¹⁹, Kristy Crooks²⁰, Lesli A Kiedrowski²¹, Leslie J Raffel²², Ora Gordon²², Kalotina Machini²³, Robert J Desnick²⁴, Leslie G Biesecker²⁵, Steven A Lubitz²⁶, Surabhi Mulchandani²⁷, Greg M Cooper²⁸, Steven Joffe²⁹, C Sue Richards³⁰, Yaoping Yang³¹, Jerome I Rotter¹⁹, Stephen S Rich³², Christopher J O'Donnell³³, Jonathan S Berg¹⁸, Nancy B Spinner¹⁴, James P Evans¹⁸, Stephanie M Fullerton³⁴, Kathleen A Leppig³⁵, Robin L Bennett¹, Thomas Bird³⁶, Virginia P Sybert³⁷, William M Grady³⁸, Holly K Tabor³⁹, Jerry H Kim⁴⁰, Michael J Bamshad⁴¹, Benjamin Wilfond⁴², Arno G Motulsky⁶, C Ronald Scott⁴³, Colin C Pritchard⁴, Tom D Walsh¹, Wylie Burke⁴⁴, Wendy H Raskind⁴⁵, Peter Byers⁵, Fuki M Hisama¹, Heidi Rehm⁴⁶, Debbie A Nickerson³, Gail P Jarvik⁶

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
² 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;
³ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
⁴ Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
⁵ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
⁶ 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;
⁷ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁸ Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁹ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
¹⁰ Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
¹¹ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98195, USA;
¹² 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;
¹³ The Framingham Heart Study, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts 01702, USA;
¹⁴ 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;
¹⁵ 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;
¹⁶ Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
¹⁷ Partners Healthcare Personalized Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
¹⁸ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
¹⁹ Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
²⁰ Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA;
²¹ Department of Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
²² Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA;
²³ 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;
²⁴ Department of Genetic and Genomic Medicine, Division of Medical Genetics, Mount Sinai Hospital, New York, New York 10029, USA;
²⁵ Genetic Diseases Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA;
²⁶ Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
²⁷ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
²⁸ HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
²⁹ Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
³⁰ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239, USA;
³¹ Department of Pediatrics, Division of Infectious Disease, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
³² Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA;
³³ 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;
³⁴ Department of Bioethics and Humanities, University of Washington, Seattle, Washington 98195, USA;
³⁵ Genetic Services, Group Health Cooperative, Seattle, Washington 98112, USA;
³⁶ 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;
³⁷ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Dermatology, Group Health Cooperative, Seattle, Washington 98112, USA;
³⁸ 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;
³⁹ 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;
⁴⁰ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA;
⁴¹ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁴² 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.
⁴³ 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;
⁴⁴ 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;
⁴⁵ 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;
⁴⁶ Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;

PMID: 25637381
PMCID: PMC4352885
DOI: 10.1101/gr.183483.114

Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Laura M Amendola et al. Genome Res. 2015 Mar.

. 2015 Mar;25(3):305-15.

doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

Authors

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
² 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;
³ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
⁴ Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
⁵ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
⁶ 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;
⁷ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁸ Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁹ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
¹⁰ Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
¹¹ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98195, USA;
¹² 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;
¹³ The Framingham Heart Study, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts 01702, USA;
¹⁴ 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;
¹⁵ 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;
¹⁶ Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
¹⁷ Partners Healthcare Personalized Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
¹⁸ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
¹⁹ Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
²⁰ Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA;
²¹ Department of Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
²² Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA;
²³ 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;
²⁴ Department of Genetic and Genomic Medicine, Division of Medical Genetics, Mount Sinai Hospital, New York, New York 10029, USA;
²⁵ Genetic Diseases Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA;
²⁶ Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
²⁷ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
²⁸ HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
²⁹ Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
³⁰ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239, USA;
³¹ Department of Pediatrics, Division of Infectious Disease, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
³² Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA;
³³ 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;
³⁴ Department of Bioethics and Humanities, University of Washington, Seattle, Washington 98195, USA;
³⁵ Genetic Services, Group Health Cooperative, Seattle, Washington 98112, USA;
³⁶ 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;
³⁷ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Dermatology, Group Health Cooperative, Seattle, Washington 98112, USA;
³⁸ 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;
³⁹ 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;
⁴⁰ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA;
⁴¹ Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
⁴² 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.
⁴³ 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;
⁴⁴ 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;
⁴⁵ 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;
⁴⁶ Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;

PMID: 25637381
PMCID: PMC4352885
DOI: 10.1101/gr.183483.114

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.

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Figures

**Figure 1.**
Variants reviewed and classifications in actionable ACMG and non-ACMG genes: (P) pathogenic; (LP) likely pathogenic; (VUS) variant of uncertain significance; (LB) likely benign; (EP) expected pathogenic.

**Figure 2.**
GERP versus CADD scores of pathogenic, likely pathogenic, and likely benign nondisruptive variants for dominant disorders. Likely benign variants with a GERP score of less than −1.0 are shown with their corresponding CADD scores along the −1 x-axis. Their true coordinates are (GERP, CADD): (−7.77, 0.15), (−7.34, 0.00), (−5.43, 1.93), (−4.01, 11.16), (−2.76, 8.66), (−2.25, 0.66).

See this image and copyright information in PMC

References

1. American College of Medical Genetics and Genomics 2014. ACMG updates recommendation on “opt out” for genome sequencing return of results. https://www.acmg.net/docs/Release_ACMGUpdatesRecommendations_final.pdf.
1. Berg JS, Amendola LM, Eng C, Van Allen E, Gray SW, Wagle N, Rehm HL, DeChene ET, Dulik MC, Hisama FM, et al. . 2013. Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet Med 15: 860–867. - PMC - PubMed
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Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Affiliations

Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases