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Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results†

  1. Sharon E. Plon1,11,‡,*,
  2. Diana M. Eccles2,‡,
  3. Douglas Easton3,
  4. William D. Foulkes4,
  5. Maurizio Genuardi5,12,
  6. Marc S. Greenblatt6,
  7. Frans B.L. Hogervorst7,
  8. Nicoline Hoogerbrugge8,
  9. Amanda B. Spurdle9,
  10. Sean V. Tavtigian10

Article first published online: 24 OCT 2008

DOI: 10.1002/humu.20880

Issue

Human Mutation

Human Mutation

Special Issue: Special Issue: Assessing Mutation Pathogenicity in Cancer Susceptibility Genes

Volume 29, Issue 11, pages 1282–1291, November 2008

Additional Information

How to Cite

Plon, S. E., Eccles, D. M., Easton, D., Foulkes, W. D., Genuardi, M., Greenblatt, M. S., Hogervorst, F. B.L., Hoogerbrugge, N., Spurdle, A. B. and Tavtigian, S. V. (2008), Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat., 29: 1282–1291. doi: 10.1002/humu.20880

Author Information

  1. 1

    Department of Pediatrics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas

  2. 2

    School of Medicine, University of Southampton, Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom

  3. 3

    Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  4. 4

    Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada

  5. 5

    Medical Genetics Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy

  6. 6

    Department of Medicine and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont

  7. 7

    DNA-Diagnostic Laboratory of the Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

  8. 8

    Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

  9. 9

    Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia

  10. 10

    International Agency for Research on Cancer; Lyon, France

  11. 11

    Department of Molecular and Human Genetics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas

  12. 12

    Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy

  1. ‡

    Sharon E. Plon and Diana M. Eccles contributed equally to this work.

*FACMG, MC3-3320; 6621 Fannin St., Houston, TX 77030

  1. †

    For the Mutation Pathogenicity Special Issue

  2. ‡

    Sharon E. Plon and Diana M. Eccles contributed equally to this work.

  3. The members of the Working Group are listed in the Appendix.

Publication History

  1. Issue published online: 24 OCT 2008
  2. Article first published online: 24 OCT 2008
  3. Manuscript Accepted: 21 JUL 2008
  4. Manuscript Received: 22 MAY 2008

Funded by

  • Australian National Health Medical Research Council
  • Canadian Breast Cancer Research Alliance
  • Ente Cassa di Risparmio Firenze
  • Lake Champlain Cancer Research Organization
  • National Institutes of Health (NIH). Grant Numbers: HG004064, CA 96536, CA116167

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Keywords:

  • IARC;
  • variants;
  • cancer genetics;
  • classification;
  • recommendations

Abstract

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. Hum Mutat 29(11), 1282–1291, 2008. © 2008 Wiley-Liss, Inc.

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