Genotypic and Phenotypic Characteristics of Germline TP53 Variant Carriers: Experience from Two Cancer Genetic Counseling Units

Germline TP53 pathogenic or likely pathogenic variants underlie Li–Fraumeni syndrome (LFS), but with broader use of multigene panel (MGP) testing carriers are increasingly identified outside classic criteria. We retrospectively studied 36 carriers from 18 families evaluated at two Spanish hereditary cancer units (2005–2023). Clinical data were obtained from medical records, and variants were functionally classified using the Giacomelli model and IARC thresholds as dominant-negative with loss of function (DNE_LOF), non-dominant-negative without loss of function (noDNE_noLOF), non-dominant-negative with loss of function, or not assessed. Descriptive statistics summarized the tumor spectrum and group comparisons were performed with the Mann–Whitney U test (α=0.05). Overall, 23 of 36 carriers (63.9%) developed at least one malignancy; 58.3% were female and the median age at first cancer was 36 years (range 27–54). Patients identified through MGP testing had later onset compared with those meeting clinical LFS criteria (median 42 [37–58] vs 27 [4–30] years; p=0.011). Breast cancer was the most frequent tumor (65% of first cancers, median age 37 [30–47]), whereas none of the MGP-ascertained carriers developed LFS “core” tumors (sarcoma, brain tumor, adrenocortical carcinoma). Fifteen distinct germline variants were identified; 80% were missense, mainly in exons 5–8. DNE_LOF (median 30 [25–38.5]) and not-assessed variants (32 [27–48]) were associated with earlier onset compared with noDNE_noLOF (47 [37–63]; p=0.034). Eight carriers (34.7%) developed second primaries after a median interval of 6 years, and four developed third primaries. Functional classification stratifies risk, supporting a broader TP53-related hereditary cancer syndrome and individualized surveillance.