Criteria for Clinical Reporting of Variants from a Broad Target Capture NGS Assay without Sanger Verification

Abstract

Increasing clinical interest and decreasing sequencing costs are driving the wider
\nimplementation of clinical next generation sequencing assays for the diagnosis of
\ninherited disease, including among a growing number of small to medium sized clinical
\nlaboratories. Therefore, an optimal combination of cost-effectiveness and clinical
\nspecificity is required to continue this broad adoption of genomic technology for clinical
\ndiagnosis. Sanger confirmation of all NGS variants is a common practice that increases
\nboth cost and turnaround time for clinical reporting. We reviewed 300 cases of Sanger
\nverified NGS results as well as 60 suspected (and subsequently confirmed) artifacts,
\nand developed a set of multiple criteria to report NGS variants without Sanger
\nverification with 100% accuracy. Using these criteria, we project greater than 80% of
\nclinically reported variants could be confidently released without Sanger confirmation.