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Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report
  1. Amanda B Spurdle1,
  2. Stephanie Greville-Heygate2,
  3. Antonis C Antoniou3,
  4. Melissa Brown4,
  5. Leslie Burke4,
  6. Miguel de la Hoya5,
  7. Susan Domchek6,
  8. Thilo Dörk7,
  9. Helen V Firth8,
  10. Alvaro N Monteiro9,
  11. Arjen Mensenkamp10,
  12. Michael T Parsons1,
  13. Paolo Radice11,
  14. Mark Robson12,
  15. Marc Tischkowitz13,
  16. Emma Tudini1,
  17. Clare Turnbull14,15,
  18. Maaike PG Vreeswijk16,
  19. Logan C Walker17,
  20. Sean Tavtigian18,19,
  21. Diana M Eccles2
  1. 1 Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
  2. 2 Faculty of Medicine, University of Southampton, Southampton, UK
  3. 3 Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  4. 4 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
  5. 5 Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
  6. 6 Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  7. 7 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  8. 8 Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
  9. 9 Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
  10. 10 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  11. 11 Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  12. 12 Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
  13. 13 Department of Medical Genetics, Cambridge University, Cambridge, UK
  14. 14 Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
  15. 15 William Harvey Research Institute, Queen Mary Hospital, London, UK
  16. 16 Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  17. 17 Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
  18. 18 Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah, USA
  19. 19 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
  1. Correspondence to Dr Amanda B Spurdle, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Amanda.spurdle{at} and Prof. Diana M Eccles, University of Southampton, Room AB215, MP801, Level B, South Academic Block; University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, UK; d.m.eccles{at}


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.

  • genetic variant
  • interpretation
  • reporting
  • vocabulary
  • cancer susceptibility
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  • Contributors ABS, DME conceived and implemented the study as presented in this final form. ABS, S-GH, DME provided initial versions of tables and worked examples for review by remaining authors. ABS, SG-H, ACA, MB, LB, MdlH, SD, TD, HVF, ANM, ARM, MTP, PR, MR, MT, ET, CT, MV, LCW, ST, DME all provided content relevant to their expertise, and the text was circulated over multiple iterations to reach consensus. ABS and DME collated text and tables to form the first draft of the manuscript, and all authors approved the final manuscript.

  • Funding ABS is supported by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (ID1061779). SG-H is supported by a research fellowshipfrom the Health Education England Genomics Education Programme (HEE GEP). ACA is supported by Cancer Research UK (C12292/A20861). MB and LB have been supported by the Australian NHMRC (ID1104808) and the Cancer Council Queensland (ID1044008, ID1026095). SD is supported by the Breast Cancer Research Foundation and Komen. MdlH is supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 634935 (BRIDGES), and by Spanish Instituto de Salud Carlos III (ISCIII) funding (grants PI15/00059), an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds. ANM was supported by NIH/NCI grant CA116167. MTP was supported in part by NHMRC (ID1101400). MR was funded in part through an NIH/NCI Cancer Center Support Grant P30 CA008748. PR was partially supported by the Italian Association for Cancer Research (AIRC; IG 15547). ET was supported by the Australian NHMRC (ID1104808). MPGV is supported by the Dutch Cancer Society KWF (UL2012-5649) and KWF-Pink Ribbon Research Project 11704. LCW is supported by a Rutherford Discovery Fellowship (Royal Society of New Zealand).

  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement This is not an original research article.

  • Patient consent for publication Not required.

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