Background: The use of ctDNA and next generation sequencing has unprecedented potential to improve genomic profiling and predicting actionable drug treatment in patients with metastatic breast cancer (MBC). Liquid biopsy is uniquely suited for patients where tissue biopsy is not feasible. We specifically focus on actionable variants found in liquid biopsy for MBC including bTMB and MSI. Here we report on the validation of a 56 gene sub panel for the determination of somatic mutations in MBC. Methods: Commercially available, well-characterized, biological ctDNA reference samples with allele frequency ranging from 0.5 -2.5% and bTMB scores (7 – 20) were obtained to analytically evaluate sensitivity, specificity and precision of a range of clinically significant variants (SNV, indels, fusions and copy number variants) in the TSO-500 ctDNA NGS assay. Additionally, 48 Whole blood samples from well characterized metastatic breast cancer patients and 13 healthy donors were obtained from commercial sources. cfDNA was extracted from the plasma separated from whole blood and analyzed on both TS0-500 ctDNA assay and PGDx Elio Complete. TSO-500 ctDNA sequencing data was further analyzed with the DRAGEN pipeline for variant calling and all variants were annotated and curated with the Clinical Genomic Workspace from PierianDx. PGDx utilized a proprietary pipeline and reporting of all variants detected. Results: Analytical validation determined excellent sensitivity (PPA: 99.4 – 100%), specificity (NPA: 99.6 -99.8%) and reproducibility (95 – 98.6%) for SNV, indels, fusions and Copy number variants. bTMB, with a cutoff for bTMB high as >20 mut/Mb, exhibited a sensitivity of 75% and specificity of 93.3%. Limit of detection (LOD) was established at 0.5 % VAF for SNV, Indels and fusions at a minimum read depth of 1000x. LOD for Copy number amplifications was established at 1.26-fold change or 3 copies. Clinical samples also exhibited excellent concordance across both TS0-500 ctDNA and PGDx Elo Complete. SNV, indels and copy number variants exhibited 100% (PPA) sensitivity and 99-100% Specificity (NPA). bTMB exhibited 87.5 % sensitivity and 96.22% specificity. As expected, fusions and microsatellite instability were observed in the clinical population but were rare. No reportable mutations were found in the healthy donors. Actionable mutations were reported for PIK3CA, ESR1, BRCA1 and BRCA2, TP53 and ERBB2 variants. Rare mutations in ATM, CHEC2, PALB2, FGFR1 and CCND1 were also observed. Conclusions: Clinical utility of liquid biopsy assays requires excellent sensitivity, specificity and precision. The Epic 56 gene panel has established clinical validity and high sensitivity and specificity across all relevant variants including bTMB in MBC. This clinically available NGS panel for metastatic breast cancer allows for routine genomic profiling, specifically in patients where tissue biopsy cannot be obtained.