TP53 c.309C>G, p.Tyr103Ter
NM_000546.6:c.309C>G
COSMIC ID: COSM44453, COSM5009795
Pathogenic
The p.Y103* truncating variant introduces a premature stop codon upstream of the NMD threshold and is absent from population databases. VCEP criteria support PVS1 (Very Strong) and PM2 (Supporting), with additional PP5 (Supporting). Per TP53 VCEP pathogenicity rules, PVS1 plus additional criteria justify a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
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_000546.6:c.309C>G
Protein Change
Y103*
Location
Exon 4
(Exon 4 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM44453, COSM5009795
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.309C>G
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Tyr103*) 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: 28681140). ClinVar contains an entry for this variant (Variation ID: 822878). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The TP53 Y103* variant is a truncating mutation that results in a premature stop codon, leading to the production of a truncated protein. Functional evidence indicates that truncating mutations in TP53 generally result in loss of protein function, promoting cancer cell proliferation, survival, and metastasis. Although Y103* has not been specifically biochemically characterized, it is predicted to be inactivating 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: 6.97
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: "Nonsense or frameshift variants predicted to undergo NMD (upstream of p.Lys351) apply PVS1 at Very Strong strength." The NM_000546.6:c.309C>G (p.Y103*) variant introduces a premature stop codon at amino acid 103, well upstream of p.Lys351, predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: PS1 applies to variants resulting in the same amino acid change as a previously established TP53 pathogenic variant. The p.Y103* variant is a novel truncating change, not a reversion to a known pathogenic amino acid substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: PS2 applies when confirmed de novo with parental testing. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP caveat: "PS3 should not be applied at any strength if PVS1 is applied at full strength." PVS1 has been applied at Very Strong strength. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: PS4 requires statistically increased prevalence of variant in affected individuals. No case–control or proband point data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: PM1 applies to germline missense variants at defined DNA-binding domain hotspots. p.Y103* is a truncating variant, not missense. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "PM2_Supporting: allele frequency <0.00003 in gnomAD or other large database." The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG: PM3 applies to recessive disorders with trans observations. TP53 disorders are dominant and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG: PM4 applies to protein length changes in in-frame indels or stop-loss. This is a stop-gain variant. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5 applies to missense variants at residues with other pathogenic missense changes. p.Y103* is truncating, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: PP1 applies when cosegregation is observed in families. No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG: PP2 applies for missense in genes with low benign missense rate. p.Y103* is a truncating variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP caveat: "PP3 should not be used in combination with PVS1." PVS1 is applied at full strength. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: PP4 applies when a specific phenotype is highly predictive for a gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG: "PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation." ClinVar lists this variant as Pathogenic by five laboratories. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: BA1 requires allele frequency ≥0.001. The variant is absent in population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: BS1 applies for filtering AF ≥0.0003 but <0.001. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: BS2 requires ≥8 unaffected older females. No such data. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 applies when functional assays show no loss of function. No such data. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: BS4 applies with lack of segregation in affected family members. No data available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG: BP1 applies to missense in gene where only truncating variants cause disease. p.Y103* is truncating, so BP1 is not applicable. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG: BP2 applies when in trans with a pathogenic variant in dominant disorders. Not applicable. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG: BP3 applies to in-frame indels in repetitive regions. Not applicable. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: BP4 applies to missense or splice predictions. p.Y103* is a stop-gain, so BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG: BP5 applies when variant found in a case with an alternate molecular basis. No such data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG: BP6 applies to reputable source reporting benign without evidence. Not relevant. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: BP7 applies to silent or intronic variants with no splice impact. p.Y103* is coding nonsense. Therefore, BP7 is not applied.