MDS-287 Genetic Landscape of Somatic Myeloid Mutations in the Presence of Rare TERT Variants and Their Relation to Myeloid Neoplasia

Alejandro Ferrer, Abhishek M. Mangaonkar, Terra L. Lasho, Mark E. Wylam, Christy M. Finke, Jenna A. Fernandez, Rong He, David S. Viswanatha, Mrinal M. Patnaik

Research output: Contribution to journalArticlepeer-review


Context: Germline variants in the TERT gene may lead to impaired telomere maintenance implicated in the pathogenesis of myelodysplastic syndromes (MDS) by unknown mechanisms. Objective: To explore the clinical and genetic associations of germline TERT variants in patients with suspicion of myeloid neoplasm. Design: We selected patients tested through our institutional amplicon-based sequencing panel (42 myeloid genes, including exons 2 to 16 of TERT, read depth >250X) that carried a TERT variant with allele frequency between 35% and 65%. Variants were classified into those with CADD score?>20 and <20 to identify the top 1% according to predicted deleteriousness. Results were correlated with MDS diagnosis and clinical and survival information. Setting: Division of Hematology (Mayo Clinic). Research protocol approved by Institutional Review Board. Patients: Unselected cohort of patients screened with a myeloid mutation gene panel due to clinical suspicion of myeloid neoplasia. Results: 55 different TERT variants (46 missense, 3 splice sites, 4 synonymous, and 2 in-frame deletions) were identified in 148 individuals from April 2016 to November 2021. None of these patients were diagnosed with a telomere biology disorder and no telomere length measurement was available. All variants were clinically classified as uncertain significance. 17 (12%) patients carried CADD>20 TERT variants of which, 59% (10 patients) were diagnosed with MDS. [5 with <5% bone marrow blasts (4 with normal karyotype) and 5 with 5-19% blasts (all with complex karyotype)] This percentage was higher compared to CADD<20 TERT carriers (34%, 49 patients, p=0.048 by Chi-square test). No major differences were found in age at diagnosis (median 70 vs 73-year-old, p=0.2305), AML-free survival (median 10 vs 15.5 months since diagnosis, p=0.4674), or percentage of carriers of additional variants in myeloid-related genes (60% vs 64%). The most frequently mutated genes in CADD>20 carriers were TP53 (22%), TET2 (18%) and RUNX1 (9%) while in CADD<20 carriers were TET2 (14%), ASXL1 (11%), and SRSF2 (9%). TP53 variants were significantly enriched in CADD>20 TERT carriers. (22.7% vs 7.4%, p=0.0169) Conclusions: CADD>20 TERT variant carriers were more likely to be associated with a diagnosis of MDS and with somatic TP53 mutations than CADD<20 carriers.

Original languageEnglish (US)
Pages (from-to)S309
JournalClinical Lymphoma, Myeloma and Leukemia
StatePublished - Oct 2022


  • MDS
  • TERT
  • TP53
  • Telomere
  • next-generation sequencing

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research


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