Objective: Sarcomas are rare cancers that develop in the bones and soft tissues, including fat, muscles, blood vessels, nerves, deep skin tissues, and fibrous tissues. Most sarcomas have no known cause although there are several factors that can increase a person’s risk of developing sarcoma, such as genetic predisposition due to the family history, previous history of radiation therapy, chemical exposure, and long-term swelling. The causes and genetic basis of sarcomas are not fully elucidated. Materials and Methods: Whole-exome sequencing (WES) was performed in patients selected from 2 different families, who were thought to be at high risk, with various sarcoma diagnoses in their families, to determine which gene or genes caused the disease. Results: At the end of the study, a total of 17 variants with a pathogenic record in the first family were identified, while a total of 8 pathogenic variants belonging to 7 different genes, including KLKB1, IRGM, PRSS1, MBL2, PTPRJ, FGFR4 and SLC34A3, were associated with various cancer risks. In the second family, 4 pathogenic variants belonging to 4 different genes, namely FGFR4, MBL2, MUTYH, and NQO1, have been identified. Conclusion: The examination of people at high risk for sarcoma and the discovery of genes that may be associated with the disease made important contributions to the follow-up protocol of both patients and risky family members. In addition, according to the results obtained, family members with cancer predisposition were selected after the risk analysis made in the families, and the necessary tests and screenings were recommended in order to provide the advantage of early diagnosis.