The present disclosure provides systems and methods to detect somatic or germline variants from cell-free DNA (cfDNA). Generally, the systems and methods comprise receiving sequencing information from cfDNA from said subject, said sequencing information comprising cfDNA sequencing reads from said plurality of genomic loci; determining quantitative allele fraction (AF) measures for each of said plurality of genomic loci based on said cfDNA sequencing reads; determining a standard deviation (STDEV) for each of said AF measures; providing a STDEV threshold and an AF threshold; determining whether each of said AF measures has a STDEV above or below said STDEV threshold; determining whether each of said AF measures is above or below said AF threshold; and classifying each locus with a STDEV below said STDEV threshold and an AF measure below said AF threshold below as being of somatic origin or classifying each locus with a STDEV below said STDEV threshold and an AF measure above said AF threshold below as being of germline.
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