ClinVar Miner

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

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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162461 SCV000212818 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-28 criteria provided, single submitter clinical testing The p.T125M variant (also known as c.374C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 374. The threonine at codon 125 is replaced by methionine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration remains proficient 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). This variant has been reported in multiple individuals with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836) as well as in two individuals with childhood-onset adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52). 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.
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 pathogenic Li-Fraumeni syndrome 2020-09-17 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 (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). 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: 12826609, 16508005, Invitae). 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.
Counsyl RCV000576336 SCV000677813 likely pathogenic Li-Fraumeni syndrome 1 2016-10-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162461 SCV000691590 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-14 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID 10761705, 12826609 and IARC database, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in four individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including three individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373) and one individual affected with early-onset breast cancer (PMID 25503501). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536) and ovarian cancer (PMID: 30216591). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000237013 SCV001134868 likely pathogenic not provided 2019-02-12 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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 carcinoma 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 Breast neoplasm 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

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