The mutation status of the gene involved in early colorectal carcinogenesis and micro-invasive liquid biopsy allows detection of mutated circulating tumor DNA (ctDNA). Early detection of precancerous lesions and CRC is vital in proper treatment and hence associated to patient survival. The frequency of APC, CTNNB1, KRAS, and BRAF mutations in circulating free DNA (cfDNA) were analyzed to evaluate the performance of the mutated ctDNA in detecting polyp and adenoma using highly sensitive QClamp XNA based PCR. A total of 71 patients with low-risk adenoma or polyps were screened and there was no significant difference in the distribution of mutations gender, age, long-term medication, smoking history, alcohol drinking, and fecal occult blood. The positive predictive value (PPV) of the four genes' panel to detect low-risk adenoma and polyps was 39.44% (n = 28/71). Specifically, of all the 71 cases studied, there were 20 cases (28.2%) with APC mutations, 7 cases (9.9%) with CTNNB1 mutations, 4 cases (5.6%) with KRAS mutations, and 2 cases (2.8%) with BRAF mutations. Most mutations occurred at APC876. The four genes' panel detected by XNA-based PCR technique might be suited to efficiently and micro-invasively detect genetic alterations in cfDNA of patients with precancerous colorectal lesions.