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J Med Genet. 2019 Jun;56(6):347-357. doi: 10.1136/jmedgenet-2018-105872. Epub 2019 Apr 8.

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

Author information

Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Faculty of Medicine, University of Southampton, Southampton, UK.
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
Department of Medical Genetics, Cambridge University, Cambridge, UK.
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
William Harvey Research Institute, Queen Mary Hospital, London, UK.
Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.


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 tumour 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 among 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.


cancer susceptibility; genetic variant; interpretation; reporting; vocabulary

Conflict of interest statement

Competing interests: MR discloses the following support: Honoraria (Advisory) from AstraZeneca, Pfizer; Consulting or Advisory from McKesson, AstraZeneca; Research Funding from AstraZeneca (Institution), Myriad (Institution, in-kind), Invitae (Institution, in-kind), Pfizer (institution), AbbVie (institution), Tesaro (institution), Medivation (Institution); Travel, Accommodation, Expenses from AstraZeneca. SD discloses the following support: Honoraria (Advisory) from AstraZeneca, Clovis and Bristol-Myers Squibb.

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