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Background <p>SETD2 encodes a histone methyltransferase responsible for trimethylation of histone H3 lysine 36, a critical epigenetic modification involved in transcriptional regulation, DNA repair, and genomic stability. Germline SETD2 variants cause SETD2-related disorders characterized by neurodevelopmental delay, intellectual disability, and variable somatic features. However, the associated tumor predisposition remains incompletely defined.</p> Case Presentation <p>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 vestibular schwannoma and similar neurodevelopmental features, suggesting a hereditary disorder. Germline testing for RASopathy-associated genes was negative. Whole-exome sequencing identified a heterozygous frameshift variant in SETD2 (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), absent from population databases. Based on ACMG/AMP criteria, this variant met PVS1 and PM2 criteria and was classified as likely pathogenic. Despite multimodal therapy including surgery, radiotherapy, and chemotherapy, the disease progressed rapidly, resulting in death.</p> Conclusions <p>This case expands the phenotypic and oncologic spectrum of SETD2-related disorders and suggests a potential association between germline SETD2 variants and malignant phyllodes tumorigenesis. These findings highlight the importance of recognizing tumor risk in affected individuals and underscore the need for further investigation into cancer surveillance strategies. </p>

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A Germline SETD2 Variant and Malignant Phyllodes Tumor: Extending the Spectrum of SETD2-Related Tumor Predisposition

  • 期刊论文

  • 发表日期：

    2026年2月26日

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  • Noriko Goda,
  • Ayumi Kawamata,
  • Daiki Okamoto,
  • Tomoyuki Yoshiyama,
  • Hiroaki Niitsu,
  • Takao Hinoi,
  • Toshiyuki Yamamoto

摘要

Background

SETD2 encodes a histone methyltransferase responsible for trimethylation of histone H3 lysine 36, a critical epigenetic modification involved in transcriptional regulation, DNA repair, and genomic stability. Germline SETD2 variants cause SETD2-related disorders characterized by neurodevelopmental delay, intellectual disability, and variable somatic features. However, the associated tumor predisposition remains incompletely defined.

Case Presentation

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 vestibular schwannoma and similar neurodevelopmental features, suggesting a hereditary disorder. Germline testing for RASopathy-associated genes was negative. Whole-exome sequencing identified a heterozygous frameshift variant in SETD2 (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), absent from population databases. Based on ACMG/AMP criteria, this variant met PVS1 and PM2 criteria and was classified as likely pathogenic. Despite multimodal therapy including surgery, radiotherapy, and chemotherapy, the disease progressed rapidly, resulting in death.

Conclusions

This case expands the phenotypic and oncologic spectrum of SETD2-related disorders and suggests a potential association between germline SETD2 variants and malignant phyllodes tumorigenesis. These findings highlight the importance of recognizing tumor risk in affected individuals and underscore the need for further investigation into cancer surveillance strategies.