Compositions and methods for accurately identifying mutations

A method of assaying sample nucleic acid molecules from a subject for a target mutation, the method comprising:

• (a) joining the sample nucleic acid molecules to cypher polynucleotides to form double-stranded cypher-target nucleic acid complexes, wherein:
• (i) the joining comprises ligation;
• (ii) each cypher polynucleotide comprises a bar code sequence selected from a plurality of distinct bar code sequences;
• and
• (iii) bar code sequences alone or in combination with sample nucleic acid molecule end sequences distinguish cypher-target nucleic acid complexes from one another;
• (b) amplifying the cypher-target nucleic acid complexes to produce a plurality of cypher-target amplification products from first strands and complementary second strands of the cypher-target nucleic acid complexes;
• (c) sequencing the cypher-target amplification products to produce a plurality of first-strand sequencing reads and a plurality of second-strand sequencing reads;
• (d) grouping sequencing reads based on (i) the bar code sequences and (ii) the nucleic acid molecule sequences, wherein a group comprises first-strand sequencing reads and second-strand sequencing reads from the cypher-target amplification products of one of the cypher-target nucleic acid complexes;
• (e) generating error-corrected sequences of the sample nucleic acid molecules by comparing the first-strand sequencing reads and second-strand sequencing reads within groups of sequencing reads to distinguish erroneous nucleotides in one strand that lack a matched base change in the complementary strand;
• and
• (f) determining whether the target mutation is present in one or more of the sample nucleic acid molecules by comparing the error-corrected sequences to a reference sequence comprising the target mutation.