Abstract
Purpose
Patients with an underlying telomere biology disorder (TBD) have variable clinical
presentations, and they can be challenging to diagnose clinically. A genomic diagnosis
for patients presenting with TBD is vital for optimal treatment. Unfortunately, many
variants identified during diagnostic testing are variants of uncertain significance.
This complicates management decisions, delays treatment, and risks nonuptake of potentially
curative therapies. Improved application of functional genomic evidence may reduce
variants of uncertain significance classifications.
Methods
We systematically searched the literature for published functional assays interrogating
TBD gene variants. When possible, established likely benign/benign and likely pathogenic/pathogenic
variants were used to estimate the assay sensitivity, specificity, positive predictive
value, negative predictive value, and odds of pathogenicity.
Results
In total, 3131 articles were screened and 151 met inclusion criteria. Sufficient data
to enable a PS3/BS3 recommendation were available for TERT variants only. We recommend that PS3 and BS3 can be applied at a moderate and supportive
level, respectively. PS3/BS3 application was limited by a lack of assay standardization
and limited inclusion of benign variants.
Conclusion
Further assay standardization and assessment of benign variants are required for optimal
use of the PS3/BS3 criterion for TBD gene variant classification.
Keywords
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Article info
Publication history
Published online: December 06, 2022
Accepted:
November 30,
2022
Received in revised form:
November 28,
2022
Received:
June 28,
2022
Footnotes
Joanne Dickinson and Tracy M. Bryan contributed equally.
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
