Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000197507 | SCV000254630 | pathogenic | Li-Fraumeni syndrome | 2021-07-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr125 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25503501, 26845104, 26014290, 18511570, 16508005, 27533082, 17401428, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609). This variant has been observed to be de novo in an individual affected with clinical features of Li-Fraumeni syndrome (PMID: 29070607). ClinVar contains an entry for this variant (Variation ID: 216465). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 125 of the TP53 protein (p.Thr125Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. |
| Ambry Genetics | RCV003165469 | SCV003911999 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-13 | criteria provided, single submitter | clinical testing | The p.T125K variant (also known as c.374C>A), located in coding exon 3 of the TP53 gene, results from a C to A substitution at nucleotide position 374. The threonine at codon 125 is replaced by lysine, an amino acid with similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li-Fraumeni syndrome (Ambry internal data). This variant has been reported as a de novo finding in an individual with a personal history of colorectal cancer diagnosed at age 24 and bilateral breast cancers diagnosed at ages 31 and 34 (Renaux-Petel M et al. J Med Genet, 2018 03;55:173-180). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no 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). Another alteration at the same codon, p.T125R (c.374C>G), has been reported in several families meeting clinical criteria for Li-Fraumeni syndrome (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91; Waszak SM et al. Lancet Oncol. 2018 06;19:785-798; Li JY et al. Int J Cancer. 2019 01;144:281-289). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |