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Cancer genetics
Short report
TP53 c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma
  1. D Gareth Evans1,2,
  2. Elaine F Harkness3,
  3. Emma R Woodward1,2
  1. 1 Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
  2. 2 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
  3. 3 Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
  1. Correspondence to D Gareth Evans, Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; gareth.evans{at}mft.nhs.uk

Abstract

Germline (likely) pathogenic TP53 variants cause Li-Fraumeni syndrome (LFS), typically associated with sarcoma, brain, breast and adrenal tumours. Although classical LFS is highly penetrant, the p.R337H variant, common in Brazil, is typically associated with childhood adrenal tumours and an older onset age of other LFS tumours. Previously, we reported the finding of p.P152L in 6 children from 5 families with adrenal tumours. We have now assessed cancer risks over the subsequent 23 years, and in one further family with p.P152L. Cancer risks were compared with those in the 11 families known to our service with classical dominant negative mutations affecting neighbouring codons 245 and 248 (codon 245/248).

Compared with codon 245/248 families, we found lower age-related risks for all non-adrenal tumours in codon 152 families (p<0.0001) with an absence of breast cancer as compared with 100% penetrance by age 36 years in codon 245/248 families (p<0.0001), and lower rates of sarcoma in non-irradiated individuals (p=0.0001). Although there were more adrenal tumours in codon 152 families (6/26 individuals, 1/27 for codon 245/248), this was not significant (p=0.05).

Understanding codon-specific cancer risks in LFS is important for accurate personalised cancer risk assessment, and subsequent prevention and early detection strategies.

  • genetics, medical
  • mutation
  • heredity
  • mutation, missense

https://doi.org/10.1136/jmg-2022-109133

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    Footnotes

    • Twitter @ER_Woodward

    • Collaborators No collaborators.

    • Contributors DGE conceived the study. All authors undertook data analysis. DGE and ERW wrote the manuscript which was reviewed by all authors.

    • Funding ERW and DGE are supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-200074).

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.