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Blood-based 'liquid biopsy' is increasingly utilized in clinical care of cancer patients and fraction of tumor-derived DNA in circulation ('tumor fraction', TFx) has demonstrated clinical validity across multiple cancer types. To determine TFx, shallow whole genome sequencing of cell-free DNA can be performed from a single blood sample, using an established computational pipeline (ichorCNA), without prior knowledge of tumor mutations, in a highly cost effective manner. We describe assay validation of this approach to facilitate broad clinical application, including evaluation of assay sensitivity, precision, repeatability, reproducibility, pre-analytic factors, and DNA quality/quantity. Sensitivity to detect TFx of 3% (lower limit of detection) was 97.2%-100% at 1x and 0.1x mean sequencing depth. Precision was demonstrated on distinct sequencing instruments (Illumina HiSeqX and NovaSeq) with no observable differences. The assay achieved pre-specified 95% agreement of TFx across replicates of the same specimen (repeatability) and duplicate samples in different batches (reproducibility). Comparison of samples collected in EDTA and Streck tubes from single venipuncture in 23 patients demonstrated that EDTA or Streck tubes were comparable if processed within 8 hours. Based on a range of DNA inputs (1ng-50ng), 20ng cfDNA is preferred input, with 5ng minimum acceptable. Overall, this shallow whole genome sequencing of cell-free DNA and ichorCNA approach offers sensitive, precise, reproductible quantitation of TFx, facilitating assay application in clinical cancer care.