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

  1. Gail P. Jarvik1,2
  1. 1Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA;
  2. 2Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;
  3. 3Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA;
  4. 4Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA;
  5. 5Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
  6. 6Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA;
  7. 7Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98195, USA;
  8. 8Department of Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
  9. 9Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
  10. 10The Framingham Heart Study, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts 01702, USA;
  11. 11Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  12. 12Department of Pediatrics, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
  13. 13Laboratory of Molecular Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
  14. 14Partners Healthcare Personalized Medicine, Partners Healthcare, Boston, Massachusetts 02115, USA;
  15. 15Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
  16. 16Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
  17. 17Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA;
  18. 18Department of Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  19. 19Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA;
  20. 20Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA;
  21. 21Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
  22. 22Department of Genetic and Genomic Medicine, Division of Medical Genetics, Mount Sinai Hospital, New York, New York 10029, USA;
  23. 23Genetic Diseases Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA;
  24. 24Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  25. 25HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
  26. 26Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
  27. 27Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239, USA;
  28. 28Department of Pediatrics, Division of Infectious Disease, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrence, California 90502, USA;
  29. 29Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA;
  30. 30Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  31. 31Department of Bioethics and Humanities, University of Washington, Seattle, Washington 98195, USA;
  32. 32Genetic Services, Group Health Cooperative, Seattle, Washington 98112, USA;
  33. 33Department of Neurology, University of Washington, Seattle, Washington 98195, USA;
  34. 34Veterans Affairs Puget Sound Health Care System Geriatric Research, Education, and Clinical Center, Seattle, Washington 98108, USA;
  35. 35Dermatology, Group Health Cooperative, Seattle, Washington 98112, USA;
  36. 36Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
  37. 37Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington 98195, USA;
  38. 38Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, Seattle, Washington 98105, USA;
  39. 39Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195, USA;
  40. 40Department of Pediatrics, Division of Bioethics, University of Washington, Seattle, Washington 98195, USA
  1. Corresponding author: pair{at}u.washington.edu

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.

Footnotes

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.183483.114.

    Freely available online through the Genome Research Open Access option.

  • Received August 27, 2014.
  • Accepted December 10, 2014.

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

| Table of Contents
OPEN ACCESS ARTICLE

This Article

  1. Published in Advance January 30, 2015, doi: 10.1101/gr.183483.114 Genome Res. 25: 305-315 © 2015 Amendola et al.; Published by Cold Spring Harbor Laboratory Press

Article Category

Share

Preprint Server



Current Issue

  1. February 2024, 34 (2)
  1. Current Issue
  1. Alert me to new issues of Genome Research