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

The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA – https://enigmaconsortium.org/) is a global research active consortium in which members have expertise in developing and bringing together a robust evidence base to underpin robust clinical utilization of inherited variants in breast and ovarian cancer susceptibility genes. The consortium was created a decade ago in 2009 and initially concentrated on BRCA1 and BRCA2 broadening its perspective to other (alleged) breast cancer susceptibility genes as these have become increasingly part of the genetic testing for breast cancer offering. ENIGMA is recognized by ClinGen as the expert interpretation group for BRCA1 and BRCA2 variant interpretation assigning ENIGMA interpretations to a 3* classification.

The work described in this paper draws together a wealth of experience from ENIGMA consortium members’ activities in the field. It recognizes the widely varying perspectives on the true meaning of many of the words that we use in different fields to describe and report genetic variants. Add to this the complexity of evidencing penetrance estimates and terminology to reflect different inferences, plus the potential for misrepresentation of the literature following translation into another field of expertise and another language, the potential for the final translation of a rapidly expanding area of risk prediction to tip from benefit to harm for recipients of results is clear.  To address this, the consortium has reviewed the current use of terminology across all relevant disciplines involved in generating evidence, provided a summary description of frequently used in silico variant interpretation tools and proposed a draft framework for more consistent use of vocabulary used in research reports and in clinical reporting to facilitate a common understanding. Finally the paper sets out a tiered approach to translating cancer susceptibility genetic variants into clinical care recommendations incorporating assessment and acknowledgement of the robustness and linking level of risk to the “severity” of any clinical intervention aimed at mitigating risk. (By Dr. Amanda B Spurdle and Prof. Diana M Eccles, https://jmg.bmj.com/content/early/2019/04/08/jmedgenet-2018-105872 )

Dr. Amanda B Spurdle

Prof. Diana M Eccles

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