Aim: Many individuals die due to cancer, and both doctors and researchers work hard to offer accurate illness, diagnostic, and prognosis monitoring, as well as resistance prediction. Methods: A liquid biopsy and hereditary cancer panels were performed on 25 patients to examine the importance, spectrum, and diversity of RET germline and somatic mutations. Most of the patients visited the clinic with the diagnosis of advanced resistant cancers or hereditary cancer (MEN2). Two groups were formed: the first group was germline (n=7, 28%), and the second was somatic (n=18, 72%). For somatic, Tier I-II-III variants; for germline, pathogenic, likely pathogenic, and VUS variants have been included in the study. Results: The mean age was 54.64. There were significantly more female participants (n=14, 56%) than males (n=11, 44%). In the germline group, the most common mutation was ‘RET:c.2410G>A’. Nine mutations were nonsense or frameshift in the somatic group, and the most common mutations were ‘RET:c.2324delinsGAC’ and ‘RET:c.1784A>G’. Nonsense or frameshift RET variants showed a higher incidence in the somatic group. Conclusion: To the best of our knowledge, this is the first research to concentrate on RET mutations in the context of genetic variability between germline and somatic variants. The current study’s results indicate that patients with solid tumors, particularly breast cancer, should undergo RET sequencing to evaluate clinical features and prognosis. Discoveries about the structure and functions of RET gene will lead to more clinically relevant treatment approaches for cancer patients and will play an essential role in improving individual risk prediction, treatment, and prognosis.