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

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The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes.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

Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation

“…While the transcription activation assay for BRCA1 does not seem to discriminate between variants with intermediate risks from variants associated with high risk,29 the BRCA2 homologous recombination (HR) assay may be able to distinguish high from moderate and low/neutral as suggested by functional assessment of variant p.Y3035S 30. For genes in which pathogenic variants are clearly associated with disease risk, a two-stage reporting system has been proposed, that is, the first stage would establish pathogenicity of the variant based on multiple criteria and the second stage would denote the likely severity or clinical consequence for that variant (high, moderate or low risk) 31. Capturing the full spectrum of risk associated with distinct pathogenic variants is a critical challenge for assay development and for reporting laboratories.…”

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

“…Following this rationale, posterior probabilities of pathogenicity were not calculated for any variant with a combined LR between 0.5 and 2. Posterior probability of pathogenicity was calculated for a total of 734 variants, and classification assigned based on previously published cut‐offs proposed for the International Agency for Research into Cancer (IARC) five tier classification scheme (Plon et al, ), with some modification of terms used to describe tiers (Spurdle et al, ), namely: Class 5 Pathogenic, >0.99; Class 4 Likely Pathogenic, 0.95–0.99; Class 3 Uncertain, 0.05–0.949; Class 2 Likely Benign, 0.001–0.049; and Class 1 Benign, <0.001. The variant classifications, with breakdown of LR components and sources, have been submitted to the following databases for public display:…”

“…Posterior probability of pathogenicity was calculated for a total of 734 variants, and classification assigned based on previously published cut-offs proposed for the International Agency for Research into Cancer (IARC) five tier classification scheme (Plon et al, 2008), with some modification of terms used to describe tiers (Spurdle et al, 2019)…”

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

“…For example, in conditions where the mechanism involves gain of function, a variant may be damaging or deleterious to the organism but not to protein activity as measured in a functional assay. Establishing standardized language to describe assay readout is an important step to prevent the misinterpretation of published data and to reduce inter-laboratory discordance with respect to PS3/BS3 application [3,22].…”

“…Further granular specifications should be used to describe the "functionally abnormal" impact (i.e., complete loss of function, partial loss of function/intermediate effect/hypomorphic, gain of function, dominant-negative) as outlined by Spurdle, et al [22]. The final assessment of the evidence should take into account both the functional effect in the assay and the mechanism of disease (see below).…”