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

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results
Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results
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.
1059-7794
1282-1291
Plon, S.E.
7b3ead1a-677f-42e1-8360-93d7e4df57c8
Eccles, D.M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Easton, D.
1bccdadd-da65-418d-90ea-483a8fe7dafb
Foulkes, W.D.
4ea4fa83-219d-41e2-abb5-8cdc9374bd9a
Genuardi, M.
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Greenblatt, M.S.
e253f40c-a52f-4b1f-a890-7c085c715d43
Hogervorst, F.B.
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Hoogerbrugge, N.
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Spurdle, A.B.
79a08784-9f45-4c4f-9bd2-cf1db78f2cda
Tavtigian, S.V.
def9dc6b-d35c-4ea6-ab1c-223ea5c3f807
IARC Unclassified Genetic Variants Working Group
Plon, S.E.
7b3ead1a-677f-42e1-8360-93d7e4df57c8
Eccles, D.M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Easton, D.
1bccdadd-da65-418d-90ea-483a8fe7dafb
Foulkes, W.D.
4ea4fa83-219d-41e2-abb5-8cdc9374bd9a
Genuardi, M.
f794b93b-02b7-45de-a2ca-66be59cea500
Greenblatt, M.S.
e253f40c-a52f-4b1f-a890-7c085c715d43
Hogervorst, F.B.
79dc00b7-051c-499c-8ba4-14d0d415fd7b
Hoogerbrugge, N.
40c1f0e4-9d6d-4a1d-9b27-a442e8990073
Spurdle, A.B.
79a08784-9f45-4c4f-9bd2-cf1db78f2cda
Tavtigian, S.V.
def9dc6b-d35c-4ea6-ab1c-223ea5c3f807

Plon, S.E., Eccles, D.M., Easton, D., Foulkes, W.D., Genuardi, M., Greenblatt, M.S., Hogervorst, F.B., Hoogerbrugge, N., Spurdle, A.B. and Tavtigian, S.V. , IARC Unclassified Genetic Variants Working Group (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Human Mutation, 29 (11), 1282-1291. (doi:10.1002/humu.20880).

Record type: Article

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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Published date: October 2008

Identifiers

Local EPrints ID: 69935
URI: http://eprints.soton.ac.uk/id/eprint/69935
ISSN: 1059-7794
PURE UUID: fc43bac0-5bf8-471b-ba74-d76a4d1a5a3f
ORCID for D.M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 06 Jan 2010
Last modified: 14 Mar 2024 02:34

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Contributors

Author: S.E. Plon
Author: D.M. Eccles ORCID iD
Author: D. Easton
Author: W.D. Foulkes
Author: M. Genuardi
Author: M.S. Greenblatt
Author: F.B. Hogervorst
Author: N. Hoogerbrugge
Author: A.B. Spurdle
Author: S.V. Tavtigian
Corporate Author: IARC Unclassified Genetic Variants Working Group

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