TP53 c.430C>T, p.Gln144Ter
NM_000546.5:c.430C>T
COSMIC ID: COSM11245, COSM318146
Pathogenic
This truncating variant Q144* in TP53 results in a predicted loss-of-function via nonsense-mediated decay (PVS1_Very Strong), is absent from population databases (PM2_Supporting), and has been reported as pathogenic in reputable sources (PP5_Supporting). Together, these criteria support classification as Pathogenic.
ACMG/AMP Criteria Applied
PM2
PP5
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.430C>T
Protein Change
Q144*
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Missense Variant
Related Variants
Alternate Identifiers
COSM11245, COSM318146
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.430C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251276Alt: 0Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/251276 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The p.Q144* pathogenic mutation (also known as c.430C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 430. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was identified in an individual with a clinical diagnosis of Li-Fraumeni Syndrome (Morgan JE et al. Hum. Mutat. 2010 Apr; 31(4):484-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
This sequence change creates a premature translational stop signal (p.Gln144*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 20127978). ClinVar contains an entry for this variant (Variation ID: 634688). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
COSMIC ID
COSM11245, COSM318146
Recurrence
79 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
92
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (92 mutations).
PM1 criterion applied.
Related Variants in This Domain
Functional Summary
The TP53 Q144* variant is a truncating mutation that results in the premature termination of the TP53 protein. Functional evidence indicates that truncating mutations in TP53 generally lead to the production of truncated protein forms that are inactivating. Experimental studies have shown that such mutations promote cancer cell proliferation, survival, and metastasis, partly due to aberrant protein localization affecting cell survival pathways. Although Q144* has not been biochemically characterized specifically, it is predicted to result in a loss of TP53 protein function based on the effects of similar truncating mutations.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.28
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "PS1 Strong: same amino acid change as a previously established pathogenic variant but different nucleotide change." The evidence for this variant shows: Q144* is a nonsense change producing a premature stop codon, not a missense change at the same amino acid as another pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "PS2 Very Strong: ≥8 points for confirmed de novo occurrences." The evidence for this variant shows: no confirmed de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "PS3 should not be applied at any strength if PVS1 is applied at full strength." The evidence for this variant shows: PVS1 has been applied at Very Strong strength. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: point‐based proband/case‐control evidence (Very Strong ≥8 points, etc.). The evidence for this variant shows: no proband counts or case‐control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate: missense variants within codons 175, 245, 248, 249, 273, 282 or ≥10 somatic occurrences; Supporting: 2–9 somatic occurrences." The evidence for this variant shows: Q144* is a truncating variant outside of missense hotspot codons. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: variant allele frequency <0.00003 in gnomAD or equivalent large database." The evidence for this variant shows: the allele frequency is 0% in gnomAD (0/251,276 alleles). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: TP53‐associated disease is autosomal dominant and no trans allele data exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame indels or stop‐loss variants." The evidence for this variant shows: Q144* is a nonsense variant causing premature termination, not an in-frame indel or stop‐loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Strong: missense variant at a residue with ≥2 different pathogenic missense variants; Moderate/Supporting for fewer events." The evidence for this variant shows: Q144* is a nonsense change, not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Supporting: assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting: cosegregation in 3–4 meioses across one or more families." The evidence for this variant shows: no familial segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and common mechanism is missense." The evidence for this variant shows: Q144* is a truncating variant, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "PP3 should not be used in combination with PVS1." The evidence for this variant shows: PVS1 has been applied at Very Strong strength. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Moderate: phenotype highly specific to a single gene disorder; Supporting: observation in tumor VAF contexts." The evidence for this variant shows: no specific phenotype or VAF data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence for independent evaluation." The evidence for this variant shows: ClinVar reports Q144* as Pathogenic from two clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency ≥0.001 in any continental population database." The evidence for this variant shows: allele frequency is 0 in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Filtering allele frequency ≥0.0003 but <0.001 in a continental population." The evidence for this variant shows: allele frequency is 0 in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥8 unrelated unaffected females ≥60 years without cancer in a single source." The evidence for this variant shows: no such unaffected elderly female data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: functional assays show normal function on Kato et al. AND no LOF on another assay." The evidence for this variant shows: truncating mutations in TP53 result in loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong: lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: Q144* is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with pathogenic variant for dominant disorder or in cis with another pathogenic variant." The evidence for this variant shows: no such allele phase data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in repetitive region without known function." The evidence for this variant shows: nonsense variant, not an in‐frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Moderate: missense with BayesDel ≤–0.008 and no splicing impact OR Supporting for BayesDel <0.16 with no splicing impact." The evidence for this variant shows: Q144* is a nonsense change. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence for independent review." The evidence for this variant shows: ClinVar reports pathogenic, not benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: synonymous or intronic variant outside core splice motifs with no predicted splicing impact." The evidence for this variant shows: Q144* is a nonsense change in coding sequence. Therefore, this criterion is not applied.