YWHAE encodes a protein of the 14-3-3 family which is involved in regulation of cellular proliferation, metabolism, and differentiation. However, altered expression of 14-3-3 family proteins is associated with development and progression of cancer. The fusion between YWHAE and one of the FAM22 family members (FAM22A or FAM22B) caused by a t(10;17)(q22;p13) has been identified in the clinically aggressive, high-grade endometrial stromal sarcoma (ESS) as well as in clear cell sarcoma of the kidney (CCSK). In contrast to the classic low-grade form of ESS harboring JAZF1 gene fusions, YWHAE-FAM22 ESS display high-grade histologic features and an aggressive clinical course. Moreover, due to the lack of estrogen and progesterone receptor expression in YWHAE-FAM22 ESS, the hormonal therapy used to treat low-grade ESS is likely to be ineffective. Consequently, differentiation between YWHAE-FAM22 and JAZF1 ESS by FISH is clinically relevant to support the diagnosis and may aid in therapeutic decision making.