A method of enriching a variant of a target nucleic acid in a mixture of nucleic acids from a sample, the target nucleic acid existing in the form of two variant sequences, wherein said variants differ at a single nucleotide position, the method comprising: providing the sample that includes the target nucleic acid wherein the variant to be enriched is present in the sample in low abundance amongst a large excess of the other variant; providing an oligonucleotide that is complementary to one strand of the target nucleic acid at a concentration that is in molar excess to the target nucleic acid, wherein the oligonucleotide is attached with an affinity label and is perfectly matched at the single nucleotide position with the variant to be enriched and has a mismatch at the single nucleotide position with the other variant; providing conditions suitable for hybridization of the oligonucleotide to the target nucleic acid to generate duplex polynucleotides consisting of the oligonucleotide and one strand of either variant of the target nucleic acid; contacting the duplex polynucleotides with a mismatch intercalating compound that preferentially binds to only the duplex polynucleotides that contain a mismatch wherein said compound is further capable of catalyzing cleavage of one strand of the duplex polynucleotide at the mismatch site with light; subjecting the duplex polynucleotides to light resulting in both cleaved and uncleaved duplex polynucleotides; applying both cleaved and uncleaved duplex polynucleotides to an affinity matrix that recognizes and binds to the affinity label on the oligonucleotide; providing conditions whereby only the cleaved duplex polynucleotide is denatured and removing the denatured single strand from the affinity matrix; and providing a buffer under conditions to denature the uncleaved polynucleotide duplex; and collecting the buffer which contains one strand of the enriched variant of the target nucleic acid, wherein the mismatch intercalating compound is Rh(bpy) 2 (chrysi) 3+, Rh(bpy) 2 (phzi) 3+, or their analogs as shown in Figure 1, wherein N represents nitrogen, Rh represents rhodium, and R 1, R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, aryl, a solid support, and a linker attached with an affinity label. providing the sample that includes the target nucleic acid wherein the variant to be enriched is present in the sample in low abundance amongst a large excess of the other variant; providing an oligonucleotide that is complementary to one strand of the target nucleic acid at a concentration that is in molar excess to the target nucleic acid, wherein the oligonucleotide is attached with an affinity label and is perfectly matched at the single nucleotide position with the variant to be enriched and has a mismatch at the single nucleotide position with the other variant; providing conditions suitable for hybridization of the oligonucleotide to the target nucleic acid to generate duplex polynucleotides consisting of the oligonucleotide and one strand of either variant of the target nucleic acid; contacting the duplex polynucleotides with a mismatch intercalating compound that preferentially binds to only the duplex polynucleotides that contain a mismatch wherein said compound is further capable of catalyzing cleavage of one strand of the duplex polynucleotide at the mismatch site with light; subjecting the duplex polynucleotides to light resulting in both cleaved and uncleaved duplex polynucleotides; applying both cleaved and uncleaved duplex polynucleotides to an affinity matrix that recognizes and binds to the affinity label on the oligonucleotide; providing conditions whereby only the cleaved duplex polynucleotide is denatured and removing the denatured single strand from the affinity matrix; and providing a buffer under conditions to denature the uncleaved polynucleotide duplex; and collecting the buffer which contains one strand of the enriched variant of the target nucleic acid, wherein the mismatch intercalating compound is Rh(bpy) 2 (chrysi) 3+, Rh(bpy) 2 (phzi) 3+, or their analogs as shown in Figure 1, wherein N represents nitrogen, Rh represents rhodium, and R 1, R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, aryl, a solid support, and a linker attached with an affinity label.