Multidisciplinary Case Presentation Meeting: Variant Interpretation in Telomere Biology Disorders

Multidisciplinary Case Presentation Meeting

April 30, 2026

Variant Interpretation in Telomere Biology Disorders

This multidisciplinary case presentation meeting brought together our Centers of Excellence and external physicians from 19 international institutions to discuss complex cases requiring careful variant interpretation in telomere biology disorders.

The meeting focused on cases involving variants of uncertain significance (VUS) where available evidence is insufficient to classify a variant as benign/likely benign or pathogenic/likely pathogenic. Cases discussed centered on variants in TERT and RTEL1, two of at least 17 genes currently associated with TBDs.

Why does VUS interpretation matter?

Participants discussed the clinical challenges and impact of uncertain genetic findings:

  • Diagnostic uncertainty – A VUS may leave individuals impacted by TBD and families in diagnostic limbo, particularly when clinical features suggest a TBD but the genetic evidence remains inconclusive.
  • Risk of misdiagnosis – Overinterpreting a VUS as disease-causing may lead to an inaccurate diagnosis, inappropriate surveillance, or unnecessary changes in management.
  • Psychological burden – Uncertain results can create stress, especially when implications for prognosis, treatment, or family members are unclear.
  • Opportunity for discovery – At the same time, carefully studied VUS cases can advance understanding of TBD genetics, improve variant classification, and contribute to broader knowledge of disease-associated mutations.

Key problems to tackle

  • Determining pathogenicity – How can we distinguish a truly disease-causing variant from an incidental rare finding?
  • Functional validation – What functional assays are needed to help classify variants as benign/likely benign or pathogenic/likely pathogenic?
  • Communication – How can clinicians clearly explain the meaning, limitations, and implications of a VUS without overstating its diagnostic significance?

Key takeaways

The discussion concluded with three major points:

  1. Functional assays are critical for supporting variant classification and determining whether a variant is likely benign or likely pathogenic.
  2. Clinicians must avoid overinterpreting a VUS as a definitive diagnosis without sufficient supporting evidence.
  3. Open communication is essential to explain the meaning of a VUS, its limitations, and how uncertainty may evolve as new evidence emerges.