Fine resolution clustering of TP53 variants into functional classes predicts cancer risks and spectra among germline variant carriers

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Montellier, Emilie | Lemonnier, Nathanaël | Penkert, Judith | Freycon, Claire | Blanchet, Sandrine | Amadou, Amina | Chuffart, Florent | Fischer, Nicholas | Achatz, Maria Isabel | Levine, Arnold | Goudie, Catherine | Malkin, David | Bougeard, Gaëlle | Kratz, Christian | Hainaut, Pierre

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ABSTRACT Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to a broad spectrum of cancers caused by pathogenic TP53 germline variants. We have used a clustering approach to assign missense variants to functional classes with distinct quantitative and qualitative features based on transcriptional activity in yeast assays. Genotype-phenotype correlations were analyzed using the germline TP53 mutation database (n= 3,446) and validated in three LFS clinical cohorts (n= 821). Carriers of class A variants recapitulated all traits of fully penetrant LFS (median age at first diagnosis = 28 years). Class B carriers showed a less penetrant form (median = 33 years, p < 0.05) dominated by adrenocortical and breast cancers. Class C or D carriers had attenuated phenotypes (median = 41 years, p < 0.001) with typical LFS cancers in C and mostly non-LFS cancers in D. This new classification provides insight into structural/functional features causing pathogenicity.

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