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Evolution of germline TP53 variant classification in children with cancer

  • E. Tallis
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
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  • S. Scollon
    Affiliations
    Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

    Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX, United States
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  • D.I. Ritter
    Affiliations
    Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

    Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX, United States
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  • S.E. Plon
    Correspondence
    Corresponding author: Feigin Tower Ste 1200, 1102 Bates Ave., Houston, TX 77030.
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States

    Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

    Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX, United States
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      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)
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