Submission Details

The TP53 gene encodes p53, a protein with essential roles in genome stability and cellular functions such as cell cycle, metabolism, apoptosis, senescence and differentiation. TP53 was first reported in relation to autosomal dominant Li-Fraumeni syndrome (LFS) in 1991 (Malkin et al., 1991, PMID: 1978757; Li et al., 1998, PMID: 3409256). Numerous variants have been reported in TP53 in relation to the development of Li-Fraumeni syndrome and include missense, small duplications, small deletions, frameshift, and nonsense mutations have been reported in humans. De novo inheritance has been noted in Li-Fraumeni syndrome in 7-20% of cases (Schneider et al., PMID: 20301488). Germline pathogenic variants in TP53 occur in ~70% of individuals with LFS, defined by patterns of personal and family history of certain early onset cancers, mainly premenopausal breast cancer, bone and soft tissue sarcomas, adrenocortical carcinomas and brain tumors (PMID: 33300245). Emerging evidence also suggests the association of ovarian cancer with pathogenic TP53 variants (PMIDs: 26720728, 30733081). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern for the different cancers. Therefore, these phenotypes have been lumped into this LFS curation. The molecular mechanisms of TP53 dysfunction for all the associated disease entities listed above are either loss of function or dominant negative; both of which result in reduced (or absent) transcriptional activity and loss of the tumor suppressive function of the p53 protein function. 8 variants (missense, nonsense, frameshift, splicing) from 3 publications in TP53 are included in this curation (PMIDs: 7978053, 8118819, 15381368). Case-control studies also support the disease association (PMIDs: 26720728, 30733081). More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. This gene-disease association is also supported by experimental evidence (6 Points; PMIDs: 2046748, 9110404, 12826609, 15607980, 16131611, 29979965, 30224644). Multiple in vitro assays demonstrated the essential role of TP53 as a tumor suppressor. Animal models also showed that heterozygous mice carrying the variants identified from patients with LFS developed multiple tumors. In summary, TP53 is definitively associated with autosomal dominant Li-Fraumeni syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as definitive for Li-Fraumeni syndrome by the Hereditary Cancer GCEP on 05/13/2020 and as limited for familial ovarian cancer by the Breast/Ovarian Cancer GCEP on 01/10/2018. This re-curation was approved as definitive by the Hereditary Cancer GCEP on 3/22/2024 (SOP Version 10).