In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas

Eur J Hum Genet. 2021 Mar;29(3):489-494. doi: 10.1038/s41431-020-00781-x. Epub 2020 Dec 15.


Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • DNA-Binding Proteins / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mutation
  • Phenotype
  • Sebaceous Gland Neoplasms / genetics*
  • Sebaceous Gland Neoplasms / pathology
  • Tumor Suppressor Protein p53 / genetics*


  • DNA-Binding Proteins
  • RAD51C protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53