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Cancer genetics
Novel germline TP53 variant (p.(Phe109Ile)) confers high risk of cancer
  1. Anna Byrjalsen1,
  2. Ulrik Kristoffer Stoltze1,2,
  3. Charlotte Lautrup3,
  4. Lise Lotte Christensen4,
  5. Torben Mikkelsen5,
  6. Lisa Hjalgrim2,
  7. Jesper Sune Brok2,
  8. Christine Dahl2,
  9. Kjeld Schmiegelow2,6,
  10. Lotte Borgwardt7,
  11. Birgitte Rode Diness1,6,
  12. Thomas Van Overeem Hansen1,6,
  13. Karin A W Wadt1,6
  1. 1Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  2. 2Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  3. 3Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  4. 4Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  5. 5Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
  6. 6Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  7. 7Department of Diagnostic Radiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Dr Anna Byrjalsen; anna.byrjalsen{at}regionh.dk

https://doi.org/10.1136/jmg-2024-110255

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    Referenced paragraph

    We present five children all carrying a germline c.325T>A, p.(Phe109Ile) variant in the TP53 gene. Of these, three children have had a total of five cancers (Burkitt lymphoma, Hodgkin lymphoma, hypodiploid acute lymphoblastic leukaemia (ALL), precursor B-ALL and astrocytoma), with two being a second primary cancer before age 18. All children were conceived by the help of a sperm donor. Using the American College of Medical Genetics and Genomics (ACMG) criteria for classification of variants in TP53 (fulfilling PM2_supporting, PS3 and PS4_supporting), the variant was classified as likely pathogenic. Following the confirmed Li-Fraumeni syndrome diagnosis, the latter second primary cancer was identified asymptomatically on whole-body and central nervous system (CNS) MRI tumour surveillance.

    Main text

    In early adolescence (12‒18 years), a Danish female (case 1) was referred for genetic counselling due to suspicion of Marfan syndrome. She had a history of Burkitt lymphoma diagnosed in early childhood (2‒5 years) after presenting with swollen lymph nodes on the neck. She was treated according to the B-non-Hodgkin lymphoma protocol (BFM-2004) and was declared cancer free 6 months later. In early adolescence, a germline whole genome sequencing (WGS) was performed as part of the diagnostic work-up, which, due to her history, was expanded to include a panel of cancer predisposition syndrome genes (n=410 genes). Germline analysis of 410 cancer-related genes is standard of care for newly diagnosed patients with childhood cancer in Denmark. No variants were identified in genes associated with Marfan syndrome; however, the patient carried a variant of unknown significance c.325T>A, p.(Phe109Ile) in the DNA binding domain of the p53 protein. In conjunction with the evidence from the other cases presented below, the variant was reclassified, and the asymptomatic patient was referred to and enrolled in Li-Fraumeni syndrome (LFS)-specific tumour surveillance.1 No other likely pathogenic or pathogenic variants were …

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    Footnotes

    • Correction notice This article has been corrected since it was published online, to fix a typographical error in the title.

    • Contributors AB and KAWW conceived of the publication. AB wrote the first draft. UKS drafted figure 1. TVOH performed variant classification. AB, UKS, CL, LLC, TM, LH, JSB, CD, KS, LB, BRD, TVOH and KAWW reviewed and revised the manuscript. AB submitted the manuscript. AB is the guarantor.

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests KAWW has received payment for a lecture to Seagen Denmark Aps. The lecture addressed BRCA gene testing in patients with breast cancer. The remaining authors declare no conflicts of interest.

    • Provenance and peer review Not commissioned; externally peer reviewed.