A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition

The SETD2 gene, located on chromosome 3p21.31, encodes a histone methyltransferase responsible for trimethylation of histone H3 at lysine 36 (H3K36me3), a key epigenetic modification involved in transcriptional regulation and DNA repair. Germline SETD2 variants are known to cause SETD2-related disorders characterized by neurodevelopmental delay, intellectual disability, and variable growth abnormalities. Although the neurodevelopmental spectrum of these disorders has been well established, tumor predisposition among affected individuals remains incompletely defined.We report a 34-year-old woman with neurodevelopmental delay, intellectual disability, hypertrichosis, and café-au-lait–like pigmentation who developed a giant malignant phyllodes tumor of the breast and multiple uterine leiomyomas. Her mother had a history of vestibular schwannoma and exhibited similar physical and neurodevelopmental features. Germline testing for RASopathy-related genes was negative, while whole-exome sequencing identified a heterozygous SETD2 likely pathogenic variant (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), which was absent from population databases. According to standardized guidelines, this variant met criteria PVS1 and PM2 and was classified as “likely pathogenic.” Despite surgery, radiotherapy, and systemic chemotherapy with doxorubicin and ifosfamide, the disease progressed rapidly, resulting in death.This case broadens the oncologic spectrum of SETD2-related disorders and suggests a potential link between SETD2 germline alterations and phyllodes tumorigenesis. Greater clinical awareness and further studies are warranted to establish appropriate cancer surveillance strategies for affected individuals.