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Cited by 912BRCA gene mutations in cancerGenomics and Rare DiseasesGenetic factors in colorectal cancer

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

Open access
Plon, Sharon E., Eccles, Diana M., Easton, Douglas, Foulkes, William D., Genuardi, Maurizio, Greenblatt, Marc S., Hogervorst, Frans B.L., Hoogerbrugge, Nicoline +3 more·2008·Human Mutation
DOI 10.1002/humu.20880PMC PMC3075918
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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.

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Cited by

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Authors
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., Tavtigian, S. V., & for the IARC Unclassified Genetic Variants Working Group
Affiliations
  • Baylor College of Medicine (US)
  • Princess Anne Hospital (GB)
  • University of Cambridge (GB)
  • McGill University (CA)
  • Fondazione Farmacogenomica FiorGen (IT)
  • University of Vermont (US)
  • The Netherlands Cancer Institute (NL)
  • Radboud University Medical Center (NL)
  • QIMR Berghofer Medical Research Institute (AU)
  • Centre international de recherche sur le cancer (FR)
Corresponding author
Plon, Sharon E.
ORCID
Venue
Human Mutation
Publisher
Wiley
Published
2008-11
Volume
29
Issue
11
Pages
1282-1291
ISSN
  • 1059-7794 (ISSN-L)
  • 1098-1004
DOI
10.1002/humu.20880
PMC
PMC3075918
OpenAlex
W2084985708
Cited by
912
References
1
Citations by year
2026: 22 · 2025: 29 · 2024: 46 · 2023: 63 · 2022: 65 · 2021: 85 · 2020: 73 · 2019: 87 · 2018: 79 · 2017: 51 · 2016: 79 · 2015: 55 · 2014: 43 · 2013: 49 · 2012: 29
FWCI
10.66
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2495 d)
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
  • Cancer Research UK (10118)
  • National Human Genome Research Institute (R01HG004064, HG004064)
  • National Cancer Institute (CA116167, R55CA096536, R01CA116167, CA 96536, U01CA116167, R01CA096536)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
cancer susceptibility genes, germline mutations, variant interpretation, variants of uncertain significance, standardized reporting system, cancer predisposition syndromes, cancer risk prediction
MeSH terms
Base Sequence, Genetic Testing, Genetics, Medical, Humans, Neoplastic Syndromes, Hereditary, Risk Factors, Genetic Variation, Genetic Predisposition to Disease, Genes, Neoplasm

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