Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492075 | SCV000581125 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-02-19 | criteria provided, single submitter | clinical testing | The p.M246T variant (also known as c.737T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 737. The methionine at codon 246 is replaced by threonine, an amino acid with similar properties. This alteration was detected in one out of 765 unselected osteosarcoma cases (Mirabello L et al. J. Natl. Cancer Inst., 2015 Jul;107). Functional studies conducted in yeast show a complete loss of transactivation activity across multiple TP53 response elements (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16). Additional, studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Another alteration resulting in a different amino acid change at the same position, p.M246V, was identified by one study in two members of a single family meeting Chompet criteria for TP53 genetic testing. Both the original patient, who was diagnosed with Wilm's tumor at age 2, and her mother, who was diagnosed with cervical cancer at age 30 and a glioma at age 35, were found to carry the alteration. In addition her brother was diagnosed with adrenal cancer at age 1 (Bardeesy N et al Nat Genet. 1994 May;7(1):91-7). Based on protein sequence alignment, this amino acid position is highly 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 |
RCV000704600 | SCV000833554 | uncertain significance | Li-Fraumeni syndrome | 2024-09-23 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 246 of the TP53 protein (p.Met246Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 428886). Invitae Evidence Modeling incorporating data from in vitro 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, 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. |
| MGZ Medical Genetics Center | RCV002289671 | SCV002579331 | pathogenic | Li-Fraumeni syndrome 1 | 2021-06-22 | criteria provided, single submitter | clinical testing | |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785245 | SCV000923813 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |