Highlights
- •Reclassification of TP53 variants over time may significantly alter management.
- •Applying the Clingen VCEP specifications to 8 variants led to reclassification in six.
- •Ongoing review of variants with high prior probability of pathogenicity from cancer patients is essential.
Abstract
Li-Fraumeni syndrome, caused by germline pathogenic variants in TP53, results in susceptibility to multiple cancers. Variants of uncertain significance
(VUS) and reclassification of variants over time pose management concerns given improved
survival with cancer surveillance for LFS patients. We describe the experience of
TP53 variant reclassification at a pediatric cancer center. Methods: We reviewed medical
records (2010–2019) of 756 patients seen in Texas Children's Cancer Genetics Clinic.
We noted initial TP53 classification and any reclassifications. We then classified TP53 variants following ClinGen TP53 variant curation expert panel recommendations using data from ClinVar, medical literature
and IARC database. Results: Of 234 patients tested for TP53, 27 (11.5%) reports contained pathogenic/likely pathogenic (P/LP) variants and 7
(3)% contained VUS. By January 2022, 4 of 6 unique VUS and 2 of 16 unique P/LP variants
changed interpretations in ClinVar. Reinterpretation of these 4 VUS in ClinVar matched
clinical decision at the time of initial report. Applying TP53 VCEP specifications classified 3 VUS to P/LP/benign, and one pathogenic variant to
likely benign. Conclusions: Planned review of variant significance is essential, especially
for patients with high probability of LFS.
Keywords
Abbreviations:
LFS (Li Fraumeni Syndrome), VUS (Variant of Uncertain Significance)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: March 03, 2022
Accepted:
February 28,
2022
Received in revised form:
February 24,
2022
Received:
June 25,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
