Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000492090 | SCV000581128 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-02-21 | criteria provided, single submitter | clinical testing | The p.T125R variant (also known as c.374C>G) is located in coding exon 3 of the TP53 gene. This alteration results from a C to G substitution at nucleotide position 374. The threonine at codon 125 is replaced by arginine, an amino acid with similar properties. This variant was reported in a single individual from a cohort of 10 patients with Li Fraumeni syndrome in the United Kingdom (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91). In addition, this variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type in yeast based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Further studies in mammalian cells showed that this alteration has decreased sensitivity to radiation, decreased suppression of colony growth, and reduced induction of apoptosis compared to wild type (Menendez D et al. Mol. Cell. Biol., 2006 Mar;26:2297-308; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). 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. |
Invitae | RCV000524926 | SCV000629809 | pathogenic | Li-Fraumeni syndrome | 2019-06-26 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with arginine at codon 125 of the TP53 protein (p.Thr125Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Li-Fraumeni syndrome (PMID: 18511570, 20127978, 20522432, 29753700, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 376667). This variant has been reported to disrupt TP53 protein function (PMID: 12826609, 16508005, 27533082, 17401428). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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, 12826609). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Database of Curated Mutations |
RCV000428977 | SCV000509821 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440628 | SCV000509822 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423368 | SCV000509823 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429727 | SCV000509824 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440402 | SCV000509825 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424026 | SCV000509826 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434737 | SCV000509827 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442755 | SCV000509828 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423812 | SCV000509829 | likely pathogenic | Renal cell carcinoma, papillary, 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432131 | SCV000509830 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442833 | SCV000509831 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424710 | SCV000509832 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436286 | SCV000509833 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442028 | SCV000509834 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425385 | SCV000509835 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436088 | SCV000509836 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419630 | SCV000509837 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430321 | SCV000509838 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436638 | SCV000509839 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419385 | SCV000509840 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only |