Compositions and methods for detecting rare sequence variants

A method of identifying a sequence variant comprising:

• (a) circularizing individual polynucleotides of a plurality of polynucleotides to form a plurality of circular polynucleotides, each circular polynucleotide having a junction between a 5′ end and a 3′ end;
• (b) amplifying said plurality of circular polynucleotides of (a) to produce a plurality of amplified polynucleotides, each amplified polynucleotide having more than one copy of the circular polynucleotide;
• (c) shearing said amplified polynucleotides or a derivative thereof to produce a plurality of sheared polynucleotides, each sheared polynucleotide comprising a 5′ end shear point and a 3′ end shear point;
• (d) subjecting said plurality of sheared polynucleotides or a derivative thereof to sequencing to identify a plurality of sequence reads of said plurality of sheared polynucleotides;
• (e) comparing said plurality of sequence reads to a reference sequence to obtain a sequence difference;
• (f) calling a sequence difference as the sequence variant when the sequence difference occurs in (i) at least two copies on one sheared polynucleotide and (ii) at least two different sheared polynucleotides having different 5′ end shear points and/or 3′ end shear points.