ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.374C>T (p.Thr125Met) (rs786201057)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 26
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162461 SCV000212818 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Other data supporting pathogenic classification
University of Washington Department of Laboratory Medicine,University of Washington RCV000162461 SCV000266132 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000237013 SCV000292695 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted TP53 c.374C>T at the cDNA level, p.Thr125Met (T125M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in two children with adrenocortical carcinoma and two adults with breast cancer, but none were reported as having a family history consistent with Li-Fraumeni syndrome (Bougeard 2015, Maxwell 2015, Shirts 2016, Zerdoumi 2017). TP53 Thr125Met is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and Zerdoumi et al. (2017) identified that this variant led to decreased expression of p53 targets following DNA damage. While Perez et al. (2016) found this variant to result in decreased p21 expression, studies were performed in a mismatch-repair deficient cell line. TP53 Thr125Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may damage the nearby natural splice donor site. However, in the absence of RNA or other functional studies, the actual effect of this variant is unknown. Although published literature reports TP53 Thr125Met in individuals with Li-Fraumeni-related phenotypes and functional data suggest a damaging effect, internal clinical data are not consistent with Li-Fraumeni syndrome. Based on currently available evidence, we consider TP53 Thr125Met to be a variant of uncertain significance.
Invitae RCV000457119 SCV000545359 likely pathogenic Li-Fraumeni syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 125 of the TP53 protein (p.Thr125Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (rs786201057, ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 26845104) and adrenocortical carcinoma (PMID: 26014290). It has also been observed to segregate with Li-Fraumeni-associated cancers in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 183748). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000576336 SCV000677813 likely pathogenic Li-Fraumeni syndrome 1 2016-10-18 criteria provided, single submitter clinical testing
Color RCV000162461 SCV000691590 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000430781 SCV000509781 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441098 SCV000509782 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421688 SCV000509783 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431915 SCV000509784 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438666 SCV000509785 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421040 SCV000509786 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433024 SCV000509787 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443535 SCV000509788 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425628 SCV000509789 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432405 SCV000509790 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442735 SCV000509791 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426825 SCV000509792 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436631 SCV000509793 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419372 SCV000509794 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427448 SCV000509795 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438105 SCV000509796 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420028 SCV000509797 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428519 SCV000509798 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439150 SCV000509799 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417610 SCV000509800 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.