Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000562255 | SCV000672391 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-14 | criteria provided, single submitter | clinical testing | The p.H178P pathogenic mutation (also known as c.533A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 533. The histidine at codon 178 is replaced by proline, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein, reported to have loss of transactivation capacity, and predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). A confirmed de novo alteration at this same position (p.H178D) was reported in a child with multiple malignancies, including a rhabdomyosarcoma diagnosed at 2 years and an osteosarcoma diagnosed at 7 years (Wozniak A et al. Pediatr Hematol Oncol. 2011 May;28(4):338-43). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001216080 | SCV001387856 | uncertain significance | Li-Fraumeni syndrome | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 178 of the TP53 protein (p.His178Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 485030). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 28915717, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV003476347 | SCV004204249 | likely pathogenic | Adrenocortical carcinoma, hereditary | 2023-04-18 | criteria provided, single submitter | clinical testing |