17-7675995-G-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.374C>G(p.Thr125Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Pathogenic.
Frequency
Consequence
NM_000546.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:3
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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]. -
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. -
Hereditary cancer-predisposing syndrome Pathogenic:3
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. -
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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. -
Li-Fraumeni syndrome Pathogenic:1
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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 18511570, 20127978, 20522432, 29753700; Invitae; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 376667). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16508005, 17401428, 27533082). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
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) -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at