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INTERNATIONAL CONGRESS OF

CancerGenetics

• Title: High-grade leiomyosarcoma with constitutional homozygous PTEN p.Pro95Arg and tumor APC/NBN VUS on paired WES

• Mahnaz Mohammadi Kian,¹ Maryam Kiani,² Amir Mohammad Roshanaei zadeh,³ Yeganeh Eshaghkhani,⁴ Ahmadreza Chaleshtori,^5,* Hamidreza Moazzeni,⁶
  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. Department of Genetics, Momgene Personalized Medicine Center, Tehran, Iran
  3. Department of Genetics, Momgene Personalized Medicine Center, Tehran, Iran
  4. Department of Genetics, Momgene Personalized Medicine Center, Tehran, Iran
  5. Department of Genetics, Momgene Personalized Medicine Center, Tehran, Iran
  6. Department of Genetics, Momgene Personalized Medicine Center, Tehran, Iran
  
  
  
• Introduction: PTEN hamartoma tumor syndrome (PHTS) is associated with diverse malignancies; its role in soft-tissue sarcoma is less defined. We report paired tumor–normal whole-exome sequencing (WES) in an adult with high-grade leiomyosarcoma to clarify potential genetic contributors.
• Methods: A 55-year-old woman underwent resection of a large abdominal/retroperitoneal mass. Histopathology confirmed high-grade leiomyosarcoma (~40×20×10 cm; 35–36 mitoses/HPF; necrosis). Family history: late-onset tremor/ataxia in the father. WES was performed on peripheral blood (germline) and FFPE tumor. Variant interpretation followed ACMG/AMP 2015 criteria with population (gnomAD/ExAC/TOPMed/Iranome) and clinical databases (ClinVar/CancerVar), in-silico predictions (including CADD), and literature review.
• Results: Germline WES identified PTEN Chr10:87933043C>G (NM_000314:c.284C>G; p.Pro95Arg) in homozygous state, absent from population databases, unreported in ClinVar, CADD 25.9—classified Likely Pathogenic. Tumor WES detected two VUS: APC Chr5:112839247C>T (NM_000038:c.3653C>T; p.Thr1218Met; rs377640390), a conserved-site missense with low allele frequency, conflicting ClinVar entries and CancerVar Tier II potential; and NBN Chr8:89971232G>A (NM_001024688:c.397C>T; p.Arg133Trp; rs34767364), a conserved-site missense with allele frequency >1%, conflicting ClinVar entries, CancerVar Tier III uncertain, previously reported in breast cancer/GBM cohorts. Additional heterozygous (likely) pathogenic variants in GCDH, CNGA1, GDAP1, and MYH7 were noted as secondary findings relevant to counseling but not explanatory of the index tumor.
• Conclusion: This case highlights an unusual homozygous PTEN variant (Likely Pathogenic) in a patient with high-grade leiomyosarcoma, suggesting a constitutional cancer-predisposition context. Tumor APC and NBN variants remain of uncertain significance. Findings support PHTS-aligned genetic counseling and surveillance. Recommended next steps include orthogonal confirmation and, if feasible, segregation analysis; PTEN immunohistochemistry and pathway readouts; and periodic re-analysis as evidence evolves.
• Keywords: Leiomyosarcoma; PTEN; APC; NBN; whole-exome sequencing;