A method of differentiating tumor and non-tumor origin nucleic acid variants in a cell-free nucleic acid (cfNA) sample obtained from a test subject at least partially using a computer, the method comprising: generating or providing, by the computer, at least one tumor variant dataset comprising a population of reference tumor-related genetic variants, wherein the tumor variant dataset comprises frequency of observance data among reference samples that comprises reference bodily fluid samples and reference non-bodily fluid samples for one or more tumor-related genetic variants in the population of reference tumor-related genetic variants, and wherein the reference samples are obtained from a single reference subject and/or from different reference subjects having an identical cancer type; determining, by the computer, one or more ratios of the frequency of observance data between the reference samples for one or more tumor-related genetic variants in the population of reference tumor-related genetic variants to produce at least one mutant allele fraction variance and/or relative prevalence dataset, wherein uniformity of prevalence across cancer types, longitudinal MAF variation over time, and/or proportion in hematological cancers is utilized in conjunction with the ratios of the frequency of observance data; generating, by the computer, at least one set of probabilities of non-tumor origin from the MAF variance and/or relative prevalence dataset; and, using the set of probabilities of non-tumor origin to differentiate nucleic acid variants detected in the cfNA sample obtained from the test subject as being tumor origin nucleic acid variants or non-tumor origin nucleic acid variants. generating or providing, by the computer, at least one tumor variant dataset comprising a population of reference tumor-related genetic variants, wherein the tumor variant dataset comprises frequency of observance data among reference samples that comprises reference bodily fluid samples and reference non-bodily fluid samples for one or more tumor-related genetic variants in the population of reference tumor-related genetic variants, and wherein the reference samples are obtained from a single reference subject and/or from different reference subjects having an identical cancer type; determining, by the computer, one or more ratios of the frequency of observance data between the reference samples for one or more tumor-related genetic variants in the population of reference tumor-related genetic variants to produce at least one mutant allele fraction variance and/or relative prevalence dataset, wherein uniformity of prevalence across cancer types, longitudinal MAF variation over time, and/or proportion in hematological cancers is utilized in conjunction with the ratios of the frequency of observance data; generating, by the computer, at least one set of probabilities of non-tumor origin from the MAF variance and/or relative prevalence dataset; and, using the set of probabilities of non-tumor origin to differentiate nucleic acid variants detected in the cfNA sample obtained from the test subject as being tumor origin nucleic acid variants or non-tumor origin nucleic acid variants.