TP53 c.374C>T, p.Thr125Met
NM_000546.5:c.374C>T
COSMIC ID: COSM168302, COSM1750374
Likely Pathogenic
The TP53 T125M variant is classified as VUS. Only computational evidence (PP3 Supporting) supports pathogenicity. No VCEP-specified moderate or strong criteria are met under TP53 guidelines, and functional, population, segregation and case data are insufficient to move beyond VUS.
ACMG/AMP Criteria Applied
PP3
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.5:c.374C>T
Protein Change
T125M
Location
Exon 4
(Exon 4 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 125: T125R, T125K, T125P
Alternate Identifiers
COSM168302, COSM1750374
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.374C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00318%
Rare
Highest in Population
African/African American
0.0115%
Low Frequency
Global: 0.00318%
African/African American: 0.0115%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 31400Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00318%, 1/31400 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0115%, 1/8714 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
11 publications
Likely Pathogenic
Based on 15 submitter reviews in ClinVar
Submitter Breakdown
3 Path
11 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (11)
c.374C>T, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Threonine by Methionine at codon 125, p.(Thr125Met). This variant is found in 1/31400 alleles at a frequency of 0.003% in the gnomAD v2.1.1 database, non-cancer dataset. 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: 0.5) (PP3_moderate). Functional studies show conflicting results. Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is no evidence of a dominant negative effect and no loss of function according to Giacomelli 2018 (PMID: 30224644). At least, this variant has been reported in 10 Chompret individuals, which awards 5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 26014290, 32457520) (PS4). It has been reported in ClinVar (1x as pathogenic, 26x as likely pathogenic, 1x as uncertain significance), LOVD (1x as likely pathogenic) and CancerHotspots (16 somatic observations, PM1). Based on the currently available information, c.374C>T is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
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). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. One RNA study showed use of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373; DOI:10.7759/cureus.24602) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536, 34675114), ovarian cancer (PMID: 30216591), and bladder urothelial carcinoma (PMID: 34240179). 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.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (11 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as Likely Pathogenic (1 clinical laboratories) and as Uncertain significance (1 clinical laboratories).
COSMIC ID
COSM168302, COSM1750374
Recurrence
55 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
193
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (193 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 125: T125R, T125K, T125P
PM5 criterion applied.
Functional Summary
The TP53 T125M variant has been functionally characterized with conflicting evidence regarding its impact. In vivo studies in yeast indicate that the variant is inactivating, showing a loss of transactivational activity compared to the wildtype. Conversely, in vitro studies in human cancer cell lines suggest the variant may be neutral, as it exhibits growth suppression activity similar to the wildtype. Additional evidence indicates that the variant results in abnormal splicing and decreased transactivation activity in a reporter assay, predicting a loss of TP53 protein function. Overall, the functional evidence suggests a potential damaging effect, but with some conflicting findings.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.925
0.925
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 6.98primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies only to null variants resulting in NMD or critical splice alterations; T125M is a missense change, not a null variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires an identical amino acid change by a different nucleotide; there is no evidence of T125M encoded by another nucleotide. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence. No de novo or parental testing data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3, the rule should not be applied if functional assay evidence is conflicting. Available studies show both loss and neutral effects. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires statistical case-control data or multiple independent probands. No such data are provided. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants in TP53 hotspots (codons 175, 245, 248, 249, 273, 282) or ≥10 somatic occurrences; codon 125 is not a defined hotspot and COSMIC recurrence is zero. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2_Supporting applies if allele frequency in gnomAD is <0.00003; observed MAF is ~0.0000318, which exceeds the threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies for recessive disorders with detected trans variants; TP53 T125M is heterozygous with no recessive context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss); T125M is a missense substitution. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5_Moderate requires one different TP53 missense variant at the same residue classified as pathogenic; no such VCEP-evaluated pathogenic variant at codon 125 is documented. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo cases without confirmation; no de novo data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires familial cosegregation; no segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for missense variants in genes with low benign missense variation; TP53 has many pathogenic missense variants and no evidence supports PP2. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 is applied when multiple computational algorithms predict a deleterious effect. REVEL score of 0.93 exceeds typical deleterious thresholds. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype or family history; no such phenotypic data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is not recommended when criteria cannot be independently reviewed. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies if gnomAD filtering allele frequency ≥0.001; observed MAF is ~0.0000318, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies if filtering allele frequency ≥0.0003 and <0.001; observed MAF is ~0.0000318, below threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation of ≥2 unaffected older individuals; no such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional assays demonstrate preserved function without loss; functional evidence is conflicting. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected members; no segregation data are provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense in genes where only truncating variants cause disease; TP53 pathogenic missense are common. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 requires observation in trans with a pathogenic variant for a recessive disorder; not applicable. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions; T125M is missense. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires benign computational evidence (e.g., BayesDel ≤–0.008 and SpliceAI <0.2); available data (REVEL 0.93) predict deleterious effect. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies if variant found in cis with a pathogenic variant and disease phenotype explained by the other variant; no such data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to reputable source reporting benign without evidence; none reported. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants without splicing impact; T125M is missense. Therefore, BP7 is not applied.