TP53 -- Li-Fraumeni syndrome 1 (MIM 151623)
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:11998
TP53 was first reported in relation to autosomal dominant Li-Fraumeni syndrome in 1991 (Malkin et al., 1991, PMID: 1978757; Li et al., 1998, PMID: 3409256). Li Fraumeni is associated with increased risk of multiple pediatric and adult malignancies (see discussion below). 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., OMID: 20301488; Gene Reviews). There are several databases describing TP53 variants of interest in Li-Fraumeni Syndrome, including: (1) the TP53 database in LOVD (https://databases.lovd.nl/shared/genes/TP53) ; (2) The TP53 Website (http://p53.fr/) (Leroy et al, 2013; PMID: 23161690) which houses the IARC TP53 database (http://p53.iarc.fr/) (Olivier et al., 2002, PMID: 12007217); (3) Database of germline p53 mutations (http://stary.lf2.cuni.cz/projects/germline_mut_p53.htm); (4) The UMD TP53 website (http://www.umd.be:2072/IFAMTP53A.shtml). There is significant genetic evidence supporting this gene-disease relationship includes case-level data and segregation data and the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by expression studies and multiple animal models that get LFS associated tumors...... The molecular mechanism 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. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found no difference in molecular mechanism, inheritance pattern, or phenotypic expressivity, and therefore have lumped the above listed disease entities into the curation for TP53 in Li-Fraumeni Syndrome. 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.
Gene Clinical Validity Standard Operating Procedures (SOP) - Version 7
Literature Review:
OMIM: https://www.omim.org/entry/151623
GENEREVIEWS: https://www.ncbi.nlm.nih.gov/books/NBK1311/
Mechanism of disease causation. Germline TP53 pathogenic variants create a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. According to Zerdoumi et al [2017], "germline TP53 mutations represent a genetic permissive context facilitating malignant transformation of cells in which DNA damage has occurred."
TP53-specific laboratory technical considerations. TP53 missense variants are the variants most commonly identified in tumors and they present challenges in germline interpretation.
A recent study reported that individuals with germline TP53 pathogenic variants resulting in p53 loss of function appeared to have a more severe phenotype than individuals with pathogenic variants that caused partial deficiency of p53. ......in contract another report showed dominant-negative pathogenic variants (in which the mutated p53 protein interferes with the function of the wild type p53 protein) appeared to have more clinically severe phenotypes than did individuals with other TP53 pathogenic variants [Bougeard et al 2015]. A laboratory study also reported that dominant-negative pathogenic variants appear to cause a more profound alteration of p53 DNA binding than other pathogenic variants [Zerdoumi et al 2017].
However, the penetrance of LFS may be overestimated as more individuals recently identified with a germline TP53 pathogenic variant do not meet classic LFS or Chompret criteria due to a less striking family and personal history of cancer [Rana et al 2018]. Individuals with TP53 pathogenic variant p.Arg337His appear to have a lower lifetime risk of cancer than those with other TP53 pathogenic variants [Ferreira et al 2019].
...study of 214 families harboring 133 distinct TP53 alterations..... Of these 133 alterations, 124 were point mutations. Nine families carried distinct TP53 genomic rearrangements (two whole gene deletions, six partial deletions and one partial duplication). Functional comparison studies indicated that patients with dominant-negative-acting missense mutations had significantly earlier tumor onset, non-dominant-negative missense mutations were intermediate in severity, and loss-of-function type mutations (including nonsense, frameshift and genomic alterations) are associated with later tumor onset.... A deletion segregated with LFS in four subjects but was also identified in an unaffected 70-year old relative, indicating incomplete penetrance.
Bougeard et al, 2015, PMID 26014290
....eight patients with CNVs affecting TP53 from a cohort of 4524 patients with diverse phenotypes tested across multiple diagnostic laboratories in Canada and the US. Four patients with focal TP53 deletions (intragenic/exonic or 3? partial) were affected with early-onset cancer while four patients with non-focal deletions encompassing TP53 and additional genes in 17p13.1 (size range 543 kb to 2.4 Mb) had overlapping developmental phenotypes but did not have cancer at the age of ascertainment (Ages 3.4, 5.75, 7.58, 33.67).
Shlien et al, 2010, PMID 21056402
The spectrum of mutations shows that the majority of all germline mutations cluster in exons 5-8, however this is undoubtedly skewed because most studies only examine these exons. In our own study, of 19 mutations found to date, five fall outside these exons (26%;
Varley et al, 1997a). This finding has profound implications for genetic testing within Li-Fraumeni families, and we recommend that all exons, both coding and non-coding, plus all splice junctions and the promoter region are analysed. We have analysed all the reported germline mutations to determine the mutation type. There is no difference in the frequency of missense and nonsense mutations between Li-Fraumeni families,other types of families and individuals with no family history. In addition, there are no differences between LFS and LFL families. There are two reports of large germline deletions, one involving the whole of exon 10 (Plummer et al, 1994) and the other removing 167 bp, including part of exon 1 and intron 1 (Varley et al, 1997a). Both of these deletions were flanked by short direct repeat sequences. Thirteen other mutations involve short insertion or deletion events (Sameshima et al, 1992; Toguchida et al, 1992; Felix et al, 1993; Birch et al, 1994a; Hamelin et al, 1994; Mazoyer et al, 1994; Stolzenberg et al, 1994; Lubbe et al, 1995; Strauss et al, 1995; Felix et al, 1996; Varley et al, 1996a, 1997a).
Varley, Evans and Birch, 1997, PMID: 9218725
Rare germline variant (rs78378222) in the TP53 3' UTR - Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome. .... a rare variant that is located in the 3' untranslated region (3' UTR) of TP53, in 7 probands (5.4%) of a cohort from LFS/LFL patients without TP53 germline mutations in the coding regions.
Macedo et al, 2016, PMID: 26823150
Pilot application of harmonised terms:
Inheritance:
Autosomal Dominant
Optional Modifier -- Incomplete penetrance
Allelic requirement:
Monoallelic_aut
Disease associated variant consequences:
Decreased gene product level
Absent gene product
Altered gene product structure
Narrative summary of molecular mechanisms:
Molecular mechanism is 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. Variant classes include missense, small duplications, small deletions, frameshift, and nonsense mutations. Variants are distributed throughout the coding sequence and whole gene deletions are also documented. Some variant have been shown to have incomplete penetrance (p.Arg337His).
List variant classes in this gene proven to cause this disease:
Splice_acceptor_variant
Splice_acceptor_variant predicted to undergo NMD
Splice_donor_variant
Splice_donor_variant predicted to undergo NMD
Frameshift_variant
Frameshift_variant predicted to undergo NMD
Stop_gained
Stop_gained predicted to undergo NMD
Inframe_deletion
Inframe_insertion
Missense
3_prime_UTR_variant
Potential novel variant classes based on predicted functional consequence
Splice_region_variant
Splice_acceptor_variant predicted to escape NMD
Splice_donor_variant predicted to escape NMD
Frameshift_variant predicted to escape NMD
Start_lost
Stop_gained predicted to escape NMD
Stop_lost
5_prime_UTR_variant
Gain of upstream Start [uORF]
Gain of upstream Start [oORF]
Stop lost [uORF]
Stop lost [oORF]
Start lost [uORF]
Frameshift [uORF]
Frameshift [oORF]
Stop gained [uORF]
Not included
intron_variant