Evolution of germline TP53 variant classification in children with cancer

•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. Li-Fraumeni syndrome, cau...

Full description

Saved in:
Bibliographic Details
Published in:Cancer genetics 2022-06, Vol.264-265, p.29-32
Main Authors: Tallis, E., Scollon, S., Ritter, D.I., Plon, S.E.
Format: Article
Language:English
Subjects:
Child
Genetic Predisposition to Disease
Genetic Testing
Germ Cells
Germ-Line Mutation - genetics
Humans
LFS
Li-Fraumeni Syndrome - epidemiology
Li-Fraumeni Syndrome - genetics
Pediatric cancer predisposition syndrome
TP53
Tumor Suppressor Protein p53 - genetics
Variant reclassification
VUS
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•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. 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.
ISSN:2210-7762
2210-7770
DOI:10.1016/j.cancergen.2022.02.011