Digital PCR (dPCR) enables specific and sensitive detection of genetic alterations in oncogenes. It is particularly suited for the analysis of rare mutations in precious samples such as circulating cell-free DNA (ccfDNA) from blood and other body fluids. For reliable detection of single base exchanges at low frequency, both, a reproducibly working dPCR system and optimized PCR assays, are indispensable. Locked Nucleic Acid (LNA)-enhanced oligonucleotides with substantially high levels of affinity for their complementary sequences make these assays excellent tools for the detection and discrimination of highly similar DNA targets.