Background: Sporadic cardiac myxoma (SCM) is the most common primary tumor of the heart; however, its molecular pathogenesis remains poorly understood. Unlike the familial forms associated with the Carney complex (CNC), SCM lacks well-defined genetic alterations. Recognizing the established role of pleomorphic adenoma gene 1 (PLAG1) rearrangements in developmental syndromes with cardiac anomalies and in neoplasms characterized by prominent myxoid stroma, we investigated whether similar genetic events occur in SCM. In parallel, we evaluated MYC amplification, considering its known association with the malignant transformation in the mesenchymal tumors. Methods: We retrospectively analyzed 14 SCM cases using fluorescence Results: Classical PLAG1 break-apart signals were detected in 35.7% (5/14) of the SCMs. Atypical isolated 5' (red) and 3' (green) signals were frequently observed (64.3% and 85.7%, respectively), potentially reflecting unbalanced translocations or copy number variation. No MYC amplification was observed in any of the cases. Statistical analysis positively supported a >0.5% threshold for PLAG1 Break-Apart (PLAG1-BA). The histological features were consistent with typical SCM morphology, and there was no evidence of malignancy. Conclusion: This study reveals PLAG1 rearrangement in a subset of SCMs, suggesting potential molecular similarities with other tumors characterized by an abundant myxoid stroma. The absence of MYC amplification reinforces the benign nature of these neoplasms. These findings raise new hypotheses regarding the pathogenesis of SCM and warrant further investigation into cardiac myxoid tumors.