Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000161035 | SCV000211757 | uncertain significance | not provided | 2014-07-29 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.728T>C at the cDNA level, p.Met243Thr (M243T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, it has been reported as a somatic change in various tumor types including breast and soft tissue sarcoma according to the Catalogue of Somatic Mutations in Cancer. A prediction model based on sequence conservation and structural calculations predicted TP53 Met243Thr may impact binding with certain promoters (Carlsson 2009). TP53 Met243Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Met243Thr occurs at a position that is moderately conserved in mammals and is located in the DNA binding domain and interacts with HIPK1, ZNF385A, AXIN1, and 53BP2 SH3 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Met243Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000222280 | SCV000273434 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-16 | criteria provided, single submitter | clinical testing | The p.M243T variant (also known as c.728T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 728. The methionine at codon 243 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an individual with pineoblastoma diagnosed at age 14 (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). It has also been reported in patients with breast cancer (Park JS et al. Cancer Res Treat, 2022 Oct;54:1099-1110). This variant is located in the functionally critical DNA binding domain of the p53 protein and has been shown to be deficient in transcriptional transactivation in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ, Mol. Cancer Res. 2010 May; 8(5):701-16). Studies conducted in human cell lines indicate this alteration is proficient 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). Crystal structure analysis indicates that M243 is one of the DNA contact residues of the p53 protein (Martin AC, Hum. Mutat. 2002 Feb; 19(2):149-64). Additional studies have indicated that this residue is important for the interaction between p53 and several of its interacting proteins, such as RAD51, BclXL and 53BP2 (Friedler A,J. Biol. Chem. 2005 Mar; 280(9):8051-9. Ma B, Phys Biol 2005 Jun; 2(2):S56-66). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000686581 | SCV000814104 | uncertain significance | Li-Fraumeni syndrome | 2023-06-21 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 182936). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 243 of the TP53 protein (p.Met243Thr). |
| Baylor Genetics | RCV003462110 | SCV004206266 | uncertain significance | Adrenocortical carcinoma, hereditary | 2023-06-21 | criteria provided, single submitter | clinical testing |