Somatic TP53 variants frequently confound germ-line testing results

Genet Med. 2018 Aug;20(8):809-816. doi: 10.1038/gim.2017.196. Epub 2017 Nov 30.


Purpose: Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.

Methods: Pathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.

Results: Among 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).

Conclusion: ACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.

Keywords: Li-Fraumeni syndrome; TP53; aberrant clonal expansion; clonal hematopoiesis; somatic variant.

Publication types

  • Editorial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Genes, p53 / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing / methods*
  • Genetic Variation / genetics
  • Germ Cells
  • Germ-Line Mutation / genetics
  • Humans
  • Li-Fraumeni Syndrome / diagnosis
  • Mutation / genetics
  • Pedigree
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • TP53 protein, human
  • Tumor Suppressor Protein p53