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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Greville-Heygate, Stephanie 
Antoniou, Antonis C 
Brown, Melissa 
Burke, Leslie 

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 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The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes.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.

Description

Keywords

cancer susceptibility, genetic variant, interpretation, reporting, vocabulary, Biomarkers, Tumor, Computational Biology, Gene Expression Profiling, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Genetic Variation, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, International Classification of Diseases, Neoplasms, Germ Cell and Embryonal, Terminology as Topic, Vocabulary, Controlled

Journal Title

J Med Genet

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

56

Publisher

BMJ
Sponsorship
Cancer Research UK (20861)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)