Abstract: Soft tissue sarcoma is a rare and heterogeneous mesenchymal tumor of soft tissue, making it prone to late diagnosis. Li-Fraumeni syndrome represents the major genetic risk factor for soft tissue sarcoma. Molecularly defined, Li-Fraumeni syndrome is mostly due to inherited germline pathogenic variants of TP53 gene. In addition to TP53, germline pathogenic variants in CHEK2 and POT1 are also associated at TP53-negative Li-Fraumeni case, in particular in families with soft-tissue sarcoma cases. In this context, multigene approach could be a proven strategy to perform the genetic profile of tumor cases with personal and family history meeting Li-Fraumeni syndrome criteria. In this study, we reported the genetic analysis in a 43-year-old man with soft tissue sarcoma and family history of cancer meeting Li-Fraumeni syndrome criteria. Genetic analysis by next-generation sequencing, using clinical exome sequencing, revealed the c.1482G > C (rs767043399) CHEK2 variant. This variant has not been previously described in literature, and although there are insufficient evidences on its role in cancer disease predisposition, it has been classified as a variant of uncertain significance (class 3) based on American College of Medical Genetics guidelines and Invitae Variant Classification Sherloc criteria. No pathogenic variants of TP53 and POT1 genes have been detected. By combining the clinical picture with the genomic information provided by genetic analysis, we suggested that rs767043399 CHEK2 variant contributes to the Li-Fraumeni phenotype in our case. Overall our observations might be useful to identify specific molecular features of Li-Fraumeni syndrome cases, with implications in the clinical management of the patients and their relatives.