Variant reclassification and recontact research: A scoping review

Abstract

Purpose: A primary challenge in clinical genetics is accurate interpretation of identified variants and relaying the information to patients and providers. Inconsistencies around handling variant reclassifications and notifying patients, combined with the lack of prescriptive guidelines on re-evaluation, reanalysis, and return of variants, has created practice challenges. Although relevant empirical work has emerged, the scope and outcomes of this research have not been characterized. Methods: We conducted a systematic literature review of variant reclassification and recontact research (2013-2023) across subdisciplines of medical genetics. Of the 159 nonduplicate records screened, we summarize findings from 54 included research articles describing variant reclassification frequencies, outcomes, and stakeholder perspectives on recontact. Results: The included articles reported on active reclassification (n = 20), passive reclassification (n = 13), stakeholder surveys (n = 11), qualitative interviews (n = 7), and reanalysis of published or ClinVar data (n = 3). On average, active and passive approaches yielded different reclassification frequencies—31% and 20%, respectively, which were considerably higher than ClinVar (<0.1%-6.4%). Despite a wealth of data on individual stakeholder perspectives and opinions on reclassification, recontact, and consensus on the need for standardization in this space, opinions differ on how to develop and implement standardized processes. Conclusion: Many active reclassification studies reapplied standard variant classification guideline to previously reported variants—thus demonstrating the number of variants that would be successfully reclassified if reinterpretation and reanalysis were performed routinely. Research gaps identified include the need for understanding practices and opinions of nongenetics providers and engaging in deliberative democracy exercises to reach consensus on these issues.

Keywords

• Genetic testing
• Recontact
• Variant reclassification