Misdiagnosis of Li-Fraumeni Syndrome in a Patient With Clonal Hematopoiesis and a Somatic TP53 Mutation

Abstract

Li-Fraumeni syndrome (LFS) is a rare genetic disorder that confers a high risk of developing certain malignancies at a young age. It is caused by germline mutations in the gene and is typically diagnosed by sequencing this gene in blood cells. The presence of a mutation in approximately half of the DNA reads (allelic fraction of 50%) is an indicator of a germline mutation, such as that in LFS. Clonal hematopoiesis (CH) is an expansion of a hematopoietic clone containing a somatic driver mutation with a low allelic fraction, usually not more than 10% to 20%. This report presents a patient with fallopian tube carcinoma who underwent multigene panel testing for cancer predisposition and was found to have a mutation in the gene, c.733G>T (p.Gly245Cys). Since the mutation had an allelic fraction of approximately 50%, it was interpreted as being germline, and the patient was diagnosed as having LFS. A year later, she developed acute myelogenous leukemia. Subsequent mutational analysis showed that the mutation was absent in her benign tissue sample but present in leukemic cells. Furthermore, sequencing of the fallopian tube tumor tissue revealed a different gene mutation, c.818G>T (p.Arg273Leu). These observations confirmed that the previously identified mutation in her blood was somatic rather than germline and that she had CH at the time of genetic testing. CH can occasionally lead to a misdiagnosis of a germline mutation and a cancer predisposition syndrome that has significant implications for patients and their families. Therefore, the abnormal result of genetic testing for hereditary cancer susceptibility should be carefully interpreted when the clinical presentation is atypical, when the patient is older, when the gene in question is known to have potential germline and somatic mutations such as the gene, and when the allelic fraction is approximately 50%.

A substantial proportion of apparently heterozygousTP53pathogenic variants detected with a next‐generation sequencing hereditary pan‐cancer panel are acquired somatically

“…A previous study showed that likely somatic PVs accounted for 0.71% of all PVs identified during hereditary cancer panel testing, with somatic PVs occurring most commonly in TP53 and among older individuals (Coffee et al, ). This was consistent with previous work, which has shown that clonal expansion of blood cell subpopulations carrying somatic variants during hematopoiesis, also termed clonal hematopoiesis of indeterminate potential (CHIP), has been observed for a number of genes (Genovese et al, ; Jaiswal et al, ; Mitchell et al, ; Xie et al, ) and occurs with normal aging (Steensma et al, ). However, it was notable that in one case, the NGS allele frequency of a TP53 PV increased from less than 30% (likely somatic range) to 45% (apparent germline range) when re‐tested after 3 months (Coffee et al, ).…”

High prevalence of cancer‐associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering

“…A high predominance of these clones and insufficiently rigorous SNP analysis can lead to false interpretation. Nevertheless, most TP53 variants found in CH have an allelic frequency of less than 20%, which should avoid the classification of these variants as germline mutations (Mitchell et al, ).…”

Yes, We Can, But Should We? Ethical Considerations in Reporting Germline Findings From Paired Tumor-Normal Genomic Testing in Patients With Advanced Cancer

“…If personal/family history are inconsistent with Li-Fraumeni syndrome, the TP53 variant may instead be a manifestation of clonal hematopoiesis of indeterminate potential. 33,34 Follow-up analysis via punch biopsy and TP53 analysis on fibroblast-derived DNA and/or germline analysis in first-degree relatives would then be required to answer this question.…”