Despite an increasing demand for precision medicine enabled by NGS measurement of actionable mutations in circulating tumor DNA (ctDNA) specimens, the ability to reliably measure and report low-frequency mutations using current NGS practices is limited. Challenges include low- or poor-quality specimens and technical errors that vary among samples and mutation sites. Here, we designed synthetic internal standards (IS) and methods for their use to better control for technical error in NGS in assessment of ctDNA specimens. The goal was to determine whether this would improve quality control, resulting in increased clinical sensitivity without loss of specificity.