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Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report

Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report
Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report
The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo, and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumor DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate amongst scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.
0022-2593
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Spurdle, Amanda B.
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Greville-Heygate, Stephanie
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Antoniou, Antonis
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Brown, Melissa A.
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Burke, Leslie J.
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de la Hoya, Miguel
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Domchek, Susan M.
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Dörk, Thilo
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Firth, Helen
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Monteiro, Alvaro N.
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Parsons, Michael T.
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Robson, Mark
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Tischkowitz, Marc
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Tudini, Emma
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Turnbull, Clare
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Vreeswijk, Maaike
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Walker, Logan C.
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Tavtigian, Sean
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Eccles, Diana
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Spurdle, Amanda B.
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Greville-Heygate, Stephanie
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Antoniou, Antonis
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Brown, Melissa A.
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Burke, Leslie J.
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de la Hoya, Miguel
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Domchek, Susan M.
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Dörk, Thilo
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Firth, Helen
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Monteiro, Alvaro N.
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Parsons, Michael T.
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Radice, Paolo
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Robson, Mark
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Tischkowitz, Marc
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Tudini, Emma
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Turnbull, Clare
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Vreeswijk, Maaike
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Walker, Logan C.
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Tavtigian, Sean
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Eccles, Diana
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Spurdle, Amanda B., Greville-Heygate, Stephanie, Antoniou, Antonis, Brown, Melissa A., Burke, Leslie J., de la Hoya, Miguel, Domchek, Susan M., Dörk, Thilo, Firth, Helen, Monteiro, Alvaro N., Mensenkamp, Arjen R., Parsons, Michael T., Radice, Paolo, Robson, Mark, Tischkowitz, Marc, Tudini, Emma, Turnbull, Clare, Vreeswijk, Maaike, Walker, Logan C., Tavtigian, Sean and Eccles, Diana (2019) Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report. Journal of Medical Genetics, 1-11. (doi:10.1136/jmedgenet-2018-105872).

Record type: Article

Abstract

The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo, and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumor DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate amongst scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.

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Towards controlled terminology for reporting germline cancer susceptibility variants an ENIGMA report - Accepted Manuscript
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Accepted/In Press date: 11 February 2019
e-pub ahead of print date: 8 April 2019

Identifiers

Local EPrints ID: 428407
URI: http://eprints.soton.ac.uk/id/eprint/428407
ISSN: 0022-2593
PURE UUID: 2e30419c-4879-498e-b517-d8d7cebdeb16
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 22 Feb 2019 17:30
Last modified: 09 Jan 2022 07:44

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Contributors

Author: Amanda B. Spurdle
Author: Stephanie Greville-Heygate
Author: Antonis Antoniou
Author: Melissa A. Brown
Author: Leslie J. Burke
Author: Miguel de la Hoya
Author: Susan M. Domchek
Author: Thilo Dörk
Author: Helen Firth
Author: Alvaro N. Monteiro
Author: Arjen R. Mensenkamp
Author: Michael T. Parsons
Author: Paolo Radice
Author: Mark Robson
Author: Marc Tischkowitz
Author: Emma Tudini
Author: Clare Turnbull
Author: Maaike Vreeswijk
Author: Logan C. Walker
Author: Sean Tavtigian
Author: Diana Eccles ORCID iD

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