Li‐Fraumeni versus Pseudo‐Li‐Fraumeni Syndrome: Key Insights for Interpreting Next‐Generation Sequencing Reports in Patients with Suspected Cancer Predisposition Syndromes

Next-generation sequencing (NGS) of tumors and now circulating cell-free DNA is increasingly used to identify “actionable” genetic abnormalities. Detecting abnormalities offers opportunities for physicians and patients to qualify for therapeutic strategies that target the oncogenic lesions identified by NGS. However, NGS tumor-testing companies are not currently licensed to report germline alterations because the assays are only validated to report somatic mutations. Li-Fraumeni Syndrome (LFS) is an inherited cancer syndrome classically associated with germline TP53mutations. The resulting cancers vary among patients but include early-onset colorectal cancer (CRC) [1, 2]. Here, we report a CRC patient with a TP53 germline mutation initially considered somatic because no TP53 germline mutation was noted in the liquid biopsy (cell-free DNA) NGS assay. Upon obtaining the unreported mutation allelic frequencies (MAFs) in the germline and liquid biopsy assays, it appeared that this patient harbors a germline TP53 mutation (LFS), rather than “Pseudo-Li-Fraumeni,” as a result of a hematopoietic progenitor cell somatic (acquired) mutation. Although MAF is routinely analyzed as part of NGS sequencing (germline or biopsies), such testing is not considered validated and other methods remain more definitive for distinguishing between germline and somatic mutations.