I have a list of variants that I would like to check exist in some cell-free DNA extracted from plasma. These variants arise from DNA extracted from clinical tissue, and tumour-derived variants may appear at very low levels in the cell-free DNA extracted from the same patients. The sequencing is such (using UMIs and consensus deduplication) that one or two variant-containing fragments post-deduplication would potentially be enough to confirm the presence of ctDNA in the plasma.
I have tried running the GATK pipeline and the samtools mpileup/mutscan pipeline, and both are excellent in extracting variants with allelic fractions close to 50%, but these are likely derived from genomic cfDNA rather than circulating tumour DNA.
Is there a bioinformatic method sensitive enough to detect the one or two DNA molecules containing the variant?