Opportunistic identification of Li-Fraumeni syndrome through germline TP53 variant detection from routine tumour next-generation sequencing: An analysis of 1394 cases.
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BACKGROUND AND OBJECTIVE: Evaluation of a hybrid strategy (bioinformatics and clinical) for detecting germline pathogenic variants in TP53 from routine tumour NGS, addressing clonal haematopoiesis of indeterminate potential (CHIP) as a key confounding factor. MATERIAL AND METHODS: Retrospective analysis of 1394 cases (2019-2025). Initial filters: VAF >40%, population rarity, and ACMG pathogenicity classification. Candidate variants were further refined using the Chompret criteria, with germline confirmation via Sanger sequencing in peripheral blood. RESULTS: TP53 variants were identified in 576 (41%) cases. The bioinformatics pipeline initially flagged 222 suspected cases; clinical curation narrowed these to 14 high-suspicion cases. Of these, 12/14 (85.7%) underwent confirmatory testing, while two were lost to follow-up, introducing a verification bias that should be considered when interpreting the overall PPV. Three LFS diagnoses were confirmed (overall positive predictive value [PPV]: 21.4%; confirmation rate among tested: 25%), all in paediatric patients (two adrenocortical carcinomas and one osteosarcoma). Notably, this included a de novo case without a family history. Conversely, no adult cases were confirmed despite high VAFs, highlighting specificity issues in this demographic. The number needed to screen (NNS) to detect one LFS patient was 465. CONCLUSIONS: Our findings underscore the clinical utility of this combined approach, particularly its high efficiency in the paediatric population where it identified a de novo case missed by classical criteria. However, its utility in unselected adults appears limited without orthogonal assays to exclude CHIP, suggesting that age-specific strategies are necessary for opportunistic screening.