Introduction: Minimal residual disease (MRD) monitoring tracks the abundance of any malignant cells remaining in the body after therapeutic intervention. Currently, circulating tumor DNA (ctDNA) is a promising biomarker for MRD diagnosis. Due to low abundance of ctDNA and unique somatic variants developed from each individual, MRD diagnosis requires personalized NGS assays with high sensitivity and specificity. Methods: To address this need and empower accurate assessments of MRD, Twist Bioscience has developed the MRD Rapid 500 Panels. This product enables customers to design, manufacture and ship fully personalized MRD panels (up to 500 targets) in as little as six days. To demonstrate the detection sensitivity of Twist Rapid 500 MRD panels, we designed five custom MRD panels which specifically target somatic variants found in Breast, Lung, Colorectal Cancer, Melanoma and Renal Cell Carcinoma. Each of these MRD panels were designed to include 197 targets, with 3-5 variants per tissue origin and a selection of passenger mutations. Probe sequences of each panel were designed to incorporate the variant allele in the test sample set. To create the sample set, we blended synthetic variant sequences with fragmented cell line gDNA (NA12878) to form a contrived specimen which approximates the profile of cell-free and circulating tumor DNA. Five frequency levels were created with average variant allele frequencies (VAFs) of 0% (WT), 0.01%, 0.05%, 0.1% and 2%. Libraries were prepared with UMI adapters and target enrichment was performed using the MRD panels. They were sequenced on both Illumina NextSeq and PacBio Onso platforms. Results: With a sequencing depth of 80,000x, variant calling results revealed that an average of 20 SNV targets can be detected with confidence in the 0.01% VAF samples for each MRD panel, clearly distinguishable from the WT control samples. In addition to demonstrating the accuracy of variant calling by targeting the alternate allele, we showcase the utility of targeting a large number of variants for the detection of an MRD signature at very low levels (e.g. 0.01% VAF). Conclusion: In summary, the performance of the Twist MRD Rapid 500 Panels showed high detection sensitivity of ultra low-frequency somatic mutations.