Somatic cancer variant curation and harmonization through consensus minimum variant level data

Abstract

BackgroundTo truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice.MethodsWe developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD.ResultsAlong with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data.ConclusionsWe expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0367-z) contains supplementary material, which is available to authorized users.

Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community‐driven standards

“…MVLD formatted variants contain AMP somatic variant interpretation guidelines as one of their central fields in the “Level of Evidence” element (Li et al., 2017; Ritter et al., 2016). AMP somatic variant interpretation guidelines assign a Tier and Level to classify a somatic variant.…”

“…Briefly, MVLD is a metadata structure that guides selection of ontologies and terminologies (Ritter et al., 2016). MVLD organizes data elements into three categories: Allele Descriptive, Allele Interpretive, and Somatic Interpretive (Figure 2).…”

“…Besides the AMP cancer variant interpretation guidelines, there have been several other proposed systems for somatic cancer variant classification, which focus on variant therapeutic value (actionability), broader clinical value, or use more complex bioinformatic approaches to the problem (Hoskinson et al., 2017; Sukhai et al., 2016; Van Allen et al., 2014). Minimum variant level data (MVLD; described below and in reference) was developed by The Clinical Genome Resource (ClinGen) Somatic WG (WG) to provide a consensus‐based, lightweight, and modular format to transfer somatic variant data of clinical relevance (Ritter et al., 2016). ClinGen is a global National Institutes of Health (NIH)‐funded effort to standardize gene and variant curation, for clinically relevant genetic information, aiding in rapid communication of this information between multiple end users including clinicians, research scientists, and the public.…”

CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer

“…However, discussion and review of criteria were able to more than double this concordance, demonstrating the need for and success of open discourse in clinical variant interpretation 21 . Recently, the Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen) has published a consensus set of minimal variant-level data (MVLD) to help standardize data elements needed for curation of the clinical utility of somatic cancer variants 23 . At present, cancer variant interpretation efforts that nominally have the same goals show a remarkably low overlap in source publications cited for these interpretations (1.6–71.6%, but generally less than 25%; Supplementary Table 2).…”

Review of Clinical Next-Generation Sequencing

“…Similar criteria for somatic testing have only been available recently, and utility of these guidelines for standardizing somatic variant interpretation and reporting across laboratories remains to be evaluated. 67,68 Though there are some tools available to assist the implementation of these guidelines for variant classification, use of these guidelines is labor-intensive and we lack automated tools that can evaluate several of these criteria and support the process. 69 As diagnostic panels increase in size, the likelihood of detecting incidental findings also increases, in particular with whole genome and whole exome testing.…”