From Family History to Structural Insight: The TP53 c.1024C>T [p.(Arg342*)] Variant in Li–Fraumeni Syndrome
Year: 2026
Type: article
Abstract: Background: Li–Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous autosomal dominant hereditary cancer syndrome characterized by early-onset tumors, multiple primary cancers, and a strong family history of cancer. Unlike most hereditary cancer syndromes, LFS predisposes individuals to a broad spectrum of malignancies, including leukemia, brain tumors, soft-tissue sarcomas, breast cancer, adrenocortical carcinoma, and bone tumors. LFS is primarily associated with germline pathogenic variants in the TP53 gene. Herein, we report the clinical, genetic, and bioinformatic findings of a family with multiple early-onset LFS-associated cancers in which the pathogenic TP53 c.1024C>T, p.(Arg342*) variant was identified. Methods: DNA extracted from peripheral blood was analyzed using a 76-gene Hereditary Cancer Panel by next-generation sequencing. Variants were classified according to ACMG criteria using VarSome, Franklin, ClinVar, OMIM, PubMed, and in silico prediction tools. Wild-type TP53 structure (AF-P04637-F1) and the mutant structure were modeled, refined, and aligned using I-TASSER, ModRefiner, and UCSF Chimera to assess structural alterations. Evolutionary conservation was evaluated using ConSurf with Bayesian and maximum likelihood methods. Results: Family history revealed individuals who had previously undergone surgery for breast cancer. Subsequent cascade testing identified the TP53 variant in three relatives without a personal history of cancer, while deceased affected relatives were unavailable for testing. Conclusions: Individuals carrying pathogenic TP53 variants require genetic counseling and intensive surveillance for early cancer detection. Appropriate follow-up of cancer-free carriers may facilitate early diagnosis and reduce cancer-related mortality. Structural modeling indicated that p.(Arg342*) abolishes the TP53 tetramerization domain while preserving the DNA-binding core, suggesting that the variant acts as a null allele rather than through a dominant-negative mechanism.
Source: Biomedicines
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,137
OpenAlex ID: W7225777819
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