A method for detecting a variant sequence target polynucleotide which is present in a nucleic acid sample, comprising the steps: a) forming a single reaction mixture containing: (i) a plurality of polynucleotides from the nucleic acid sample, and (ii) a plurality of oligonucleotide tags, I. wherein individual oligonucleotide tags in the plurality of oligonucleotide tags include a region having a randomer tag sequence which comprises different random tag sequences alternating with fixed tag sequences, wherein the fixed tags sequences within the randomer tag sequence form a sequence alignment anchor, and II. the plurality of oligonucleotide tags comprise a plurality of single- or double-stranded primers, wherein individual primers include: i. a 3' region that specifically binds a target sequence in the plurality of polynucleotides from the nucleic acid sample, and ii. a 5' tail having a sequence that is not complementary to a target sequence in the plurality of polynucleotides from the nucleic acids sample, and including a sequence comprising the randomer tag sequence; and b) generating within the single reaction mixture a plurality of tagged polynucleotides by appending at least one tag from the plurality of oligonucleotide tags to individual polynucleotides within the plurality of polynucleotides; c) generating a population of tagged amplicons by amplifying the plurality of tagged polynucleotides; d) sequencing at least a portion of the population of tagged amplicons to generate a plurality of candidate sequencing reads; e) aligning the sequence alignment anchors of the plurality of candidate sequencing reads and generate error-corrected sequencing data; and f) determining that the variant sequence target polynucleotide is present in the nucleic acid sample at an abundance level of 0.05 - 5%. a) forming a single reaction mixture containing: (i) a plurality of polynucleotides from the nucleic acid sample, and (ii) a plurality of oligonucleotide tags, I. wherein individual oligonucleotide tags in the plurality of oligonucleotide tags include a region having a randomer tag sequence which comprises different random tag sequences alternating with fixed tag sequences, wherein the fixed tags sequences within the randomer tag sequence form a sequence alignment anchor, and II. the plurality of oligonucleotide tags comprise a plurality of single- or double-stranded primers, wherein individual primers include: i. a 3' region that specifically binds a target sequence in the plurality of polynucleotides from the nucleic acid sample, and ii. a 5' tail having a sequence that is not complementary to a target sequence in the plurality of polynucleotides from the nucleic acids sample, and including a sequence comprising the randomer tag sequence; and I. wherein individual oligonucleotide tags in the plurality of oligonucleotide tags include a region having a randomer tag sequence which comprises different random tag sequences alternating with fixed tag sequences, wherein the fixed tags sequences within the randomer tag sequence form a sequence alignment anchor, and II. the plurality of oligonucleotide tags comprise a plurality of single- or double-stranded primers, wherein individual primers include: i. a 3' region that specifically binds a target sequence in the plurality of polynucleotides from the nucleic acid sample, and ii. a 5' tail having a sequence that is not complementary to a target sequence in the plurality of polynucleotides from the nucleic acids sample, and including a sequence comprising the randomer tag sequence; and i. a 3' region that specifically binds a target sequence in the plurality of polynucleotides from the nucleic acid sample, and ii. a 5' tail having a sequence that is not complementary to a target sequence in the plurality of polynucleotides from the nucleic acids sample, and including a sequence comprising the randomer tag sequence; and b) generating within the single reaction mixture a plurality of tagged polynucleotides by appending at least one tag from the plurality of oligonucleotide tags to individual polynucleotides within the plurality of polynucleotides; c) generating a population of tagged amplicons by amplifying the plurality of tagged polynucleotides; d) sequencing at least a portion of the population of tagged amplicons to generate a plurality of candidate sequencing reads; e) aligning the sequence alignment anchors of the plurality of candidate sequencing reads and generate error-corrected sequencing data; and f) determining that the variant sequence target polynucleotide is present in the nucleic acid sample at an abundance level of 0.05 - 5%.