ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.374C>G (p.Thr125Arg)

dbSNP: rs786201057
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492090 SCV000581128 pathogenic Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter clinical testing The p.T125R pathogenic mutation (also known as c.374C>G), located in coding exon 3 of the TP53 gene, 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 mutation 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 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 a 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). Other 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000524926 SCV000629809 pathogenic Li-Fraumeni syndrome 2022-07-04 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16508005, 17401428, 27533082). 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: 12826609, 25503501, 26014290, 26845104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 376667). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 18511570, 20127978, 20522432, 29753700; Invitae; externalcommunication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 125 of the TP53 protein (p.Thr125Arg).
Genome-Nilou Lab RCV000492090 SCV002582406 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289540 SCV002583068 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV002289540 SCV004011719 pathogenic Li-Fraumeni syndrome 1 2023-07-10 criteria provided, single submitter clinical testing The p.T125R variant (also known as c.374C>G) is located in coding exon 4 of the TP53 gene (NM_000546.5). 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 individuals with Li Fraumeni syndrome in the UK (PMID:16508005‚ 20127978‚ 20407015). This variant submitted to ClinVar database (ID;376667) by five clinical laboratory and classified as Likely pathogenic/pathogenic .This amino acid position is highly conserved (PhyloP=7.8). Functional tests done for this variant confirm the pathogenicity (PMID: 30224644, 8023157, 12826609). In addition, this alteration is predicted to be deleterious by in silico analysis (as SIFT, CADD, M-CAP, Mutation taster and PolyPhen) . Based on these evidences this variant classified as pathogenic.
Myriad Genetics, Inc. RCV002289540 SCV004931104 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29979965].
GeneDx RCV004719815 SCV005324867 pathogenic not provided 2023-11-22 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (PMID: 12826609, 29979965, 30224644, 34675114, 27533082, 20407015, 12909720); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in several individuals with personal and family histories consistent with Li-Fraumeni syndrome tested at GeneDx and in published literature (PMID: 20522432, 34675114, 29753700); This variant is associated with the following publications: (PMID: 30840781, 20127978, 29979965, 15510160, 30224644, 33257846, 21121188, 30661751, 27533082, 26619011, 20407015, 12909720, 12826609, 34675114, 16508005, 26845104, 29753700, 29752822, 20522432, 18511570)
Molecular Diagnostics Laboratory, Catalan Institute of Oncology RCV000492090 SCV005407753 likely pathogenic Hereditary cancer-predisposing syndrome 2023-01-16 criteria provided, single submitter clinical testing c.374C>G, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Threonine by Lysine at codon 125, p.(Thr125Lys). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.59) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 2 Chompret individuals, which awards 1 point to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 20522432) (PS4_supporting). It has been reported in ClinVar, LOVD, CancerHotspots (6 somatic observations). Based on the currently available information, c.374C>G is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.

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