AMP offers evidence-based recommendations for next-generation sequencing germline variant confirmation
The Association for Molecular Pathology (AMP) has published a report that was designed to establish recommendations for standardizing orthogonal confirmation practices for germline variants detected by next-generation sequencing (NGS). The manuscript, “Recommendations for Next-Generation Sequencing Germline Variant Confirmation: A Joint Report of the Association for Molecular Pathology and National Society of Genetic Counselors,” was released online ahead of publication in The Journal of Molecular Diagnostics.
The AMP Clinical Practice Committee convened the NGS Germline Variant Confirmation Working Group to assess current evidence and standardize orthogonal confirmation practices to help limit the reporting of false positives. The new report offers the following eight recommendations that are based on a comprehensive review of published literature, empirical data, current laboratory practice surveys, feedback from open public comment, and professional experiences.
- Clinical laboratories offering germline testing using NGS should establish a written policy regarding orthogonal confirmation of NGS results.
- Laboratories’ orthogonal confirmation policy should be overseen and approved by a qualified and appropriately certified medical professional with training and experience in NGS.
- Laboratories’ confirmatory methods, platforms, and associated bioinformatics should be validated and maintained under appropriate regulatory oversight as for other aspects of the test.
- Laboratories’ confirmatory methods should be orthogonal. Discrepant results between NGS and a confirmatory assay should be investigated and resolved, rather than accepting any one methodology to be always correct.
- Laboratories should perform confirmatory testing for reported germline variants with significant clinical implications, except for variant calls meeting technical criteria rigorously demonstrated to ensure high positive predictive value from NGS alone.
- Laboratories should clearly articulate their specific policies, criteria, and methods regarding orthogonal confirmation in written materials readily available upon request.
- Laboratories’ clinical test reports should summarize orthogonal confirmation policy in every report, and when exceptions to the policy are made, these should be clearly indicated.
- Special considerations apply to certain NGS-based test types and findings.
