Liquid biopsy tests are an integral part of the molecular diagnostic workup of cancer specimens. We have performed extensive validation studies of the GeneStrat NGS test (GSNGS), that uses an NGS panel developed on semiconductor-based sequencing technology. The workflow requires very low input (20 ng) of cell-free nucleic acids and yields results in an average of three business days. GSNGS was validated for the detection of copy number amplifications (CNAs), fusions/exon skipping, somatic single nucleotide variants (SNV) and insertions/deletions (INDELs). Validation specimens included contrived and clinical samples. Dependent on the variant class we used ultrasensitive ddPCR, amplicon-based, and non-amplicon-based panels on multiple NGS platforms as orthogonal methods. All orthogonal technologies utilized the native workflows and analyses pipelines as intended by their manufacturers. We observed concordance with the GSNGS test for SNV and indels of greater than 97.7% with the orthogonal droplet digital PCR (ddPCR) test, GeneStrat ddPCR. Studies of the tested CNA and fusions/exon-skipping showed 100% concordance between GSNGS and TSO500. Accuracy studies with the two amplicon-based NGS systems (manual and automated workflows), used clinical specimens and here we observed 100% concordance in variant calls for SNVs, INDELs and fusions/exon-skipping. One CNA variant instance was observed on the manual workflow that was not called by the automated workflow (97% concordance). The high concordance of the independent workflows for the detection of nucleic acid variants in circulation demonstrates the capability of GSNGS test to be used for testing of clinical specimens. Specifically, actionable variants in the four major mutation classes were successfully detected in the reference and test specimen sets using orthogonal test methods. The validated test panel meets the criteria for being rapid, highly sensitive and specific, and has utility for the reporting of clinically re...