A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation

Abstract

PurposeGenome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder allows the possibility of clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource on the clinical relevance of genomic variation for use in precision medicine and research.MethodsWe developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semi-quantitative metric to score actionability.ResultsWe generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol which highlight important issues in characterizing actionability across a range of disorders.ConclusionThe ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

“…The SFWG acknowledged the inherent subjectivity and difficulty of rating any given intervention as it applies to an individual but voted unanimously in favor of adding this fifth criterion. This achieved consistency with efforts of the NIH-funded Clinical Genome Resource (ClinGen) 5 Actionability Working Group, 6 which had already applied these five criteria to assign actionability scores (called "Actionability Evidence-based Summaries") 7 to genes/conditions on the SF list.…”

The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients

“…Our analytic pipeline allowed for the identification of reported pathogenic variants in more than 4600 disease-associated genes but concluded with a manual review of the supporting evidence of each identified variant, allowing for variant classification using current ACMG standards and inclusion of only those variants meeting a rigorous evidence base for pathogenicity(35). The list of genes and variants considered reportable will likely change as new gene-disease associations are identified, better estimates of penetrance from unbiased samples are generated, and implications for prognosis and therapy are defined(36, 37). Indeed, the PDE11A variant (p.Thr58ProfsX41) reported to one participant was reclassified from VUS:FP to VUS after the study period and thus no longer meets MedSeq Project reporting criteria.…”

A primer to clinical genome sequencing

“…The rapid changes in our understanding of genetic disease frustrates the use of gene-panel tests; when a new gene or mechanism for disease is reported in the literature, a patient with a negative genetic test requires repeat testing with a second genetic test to include the new information. It is not difficult to imagine a future where a single comprehensive genetic test is ordered, such as genome sequencing, and the patient’s report is updated annually with new findings as our understanding of genetic diseases evolves (53,54). …”