ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26014290 Bougeard et al (2015) provided an update on Li Fraumeni syndrome (LFS), including a summary of the TP53 germline mutational spectrum from their study of 214 families harboring 133 distinct TP53 alterations, identified by Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). 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. Previous studies by this group provided further characterization of TP53 whole gene deletion: Bougeard et al., 2003 (PMID 12584563) used QMPSF to analyze the 11 exons of TP53 in 98 families with full or partial criteria for LFS for whom classical methods had not revealed TP53 alterations. In one family fulfilling the criteria for LFS, a complete heterozygous deletion (including all exons) was identified. The deletion was determined by subsequent additional QMPSF and long-range PCR to involve two adjacent regions: a 35.2 kb deletion extending from exon 6 of the gene WRAP53 (FLJ10385) and encompassing TP53 (19 kb), 352 bp of intervening sequence, and a 9.4 kb deletion partially overlapping the gene ATP1B2. The deletion segregated with LFS in four subjects but was also identified in an unaffected 70-year old relative, indicating incomplete penetrance. Zerdoumi et al, 2013 PMID: 23172776 used in vitro analyses to show a functional null effect of a subset of TP53 mutations, including complete TP53 deletion (Patient 3), and showed correlation between mutation type and age of tumor onset.
21056402 Shlien et al (2010) presented clinical findings of 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). In combination with results from gene expression studies, the authors suggest these partial TP53 deletions (none of which removed exon 1/intron1) may lead to expression of a dominant-acting truncated protein rather than being functionally null.

Haploinsufficiency phenotype comments:

TP53 encodes a transcription factor involved in diverse cellular processes including cell cycle arrest, apoptosis, senescence, DNA repair and metabolism. Constitutional (germline) mutations and copy-number alterations in TP53 are associated with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome associated with the development of soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. Patients with TP53 mutation and partial LFS features are also reported (LFS-like syndrome). The majority of germline alterations to TP53 are missense mutations, which are distributed across the gene and also in hotspots. Missense mutations appear to be associated with earlier onset of cancer. Functional studies have shown missense mutations that act by dominant-negative mechanisms of pathogenicity are most severe (see Bougeard et al., 2015 PMID 26014290, Zerdoumi et al, 2013 PMID: 23172776). Loss-of-function mutations (nonsense, frameshift) and intragenic, exonic deletions are also reported in LFS and appear to be associated with later tumor onset. Whole gene deletion in LFS is rare; of the 214 LFS families studied by Bougeard et al., 2015 (PMID 26014290), only two whole gene deletions were reported. Genotype-phenotype correlation studies have suggested that patients with larger, non-focal whole gene deletions of TP53 may be at a lowered risk for tumor formation. Additional relevant literature is summarized below: Relevance of non-focal TP53 deletion: Giordano et al., 2014 (PMID 24501763) reported a new case and reviewed the literature of 10 patients with non-focal TP53 deletions. None of the 11 patients were found to be affected with cancer at the time of ascertainment, although later onset tumor formation in these patients remains possible. The authors state that, ?Even if it is possible that associated deletions could reduce cancer risk, an accurate surveillance is still recommendable, taking into account the possibility that these patients may have a high risk of developing cancer also at later ages.? Previously cited in this review: Varley (2003, PMID 12619118) reviewed the literature (composed of ~250 germline mutations) and their experience with 48 germline mutations in TP53 associated with Li-Fraumeni syndrome. Their cohort of 48 mutations included 35 within the hotspot regions II to V (encoded by exons 5 to 8) and 13 outside coding regions of exons 5-8, including one large deletion, one complex indel, and seven splicing mutations. Genotype-phenotype analysis of families with or without germline TP53 mutations showed that mutations within the core DNA-binding domain were associated with younger age of onset for tumor formation compared to loss-of-function-type mutations (nonsense, splice, deletions, and insertions) or with no germline TP53 mutation, and that mutations within the core domain act via gain-of-function or dominantly, as supported by retention of the wild-type allele in patient tumor samples, whereas in tumors with germline loss-of-function-type mutations, the wild-type allele is inactivated or deleted.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity