TP53 c.981T>A, p.Tyr327Ter
NM_000546.6:c.981T>A
COSMIC ID: COSM4398579, COSM4398580
Pathogenic
Y327* is a premature stop codon upstream of the NMD threshold, meeting PVS1_Very Strong. It is absent from population databases (PM2_Supporting) and reported as pathogenic in ClinVar (PP5_Supporting). No other criteria apply. The combined evidence supports 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.981T>A
Protein Change
Y327*
Location
Exon 9
(Exon 9 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM4398579, COSM4398580
Variant interpretation based on transcript NM_000546.6
Genome Browser
Loading genome browser...
HGVS InputNM_000546:c.981T>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1361331). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr327*) 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).
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 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 Y327* variant is a truncating mutation in the tumor suppressor gene TP53. Functional evidence indicates that such truncating mutations lead to the production of C-terminally truncated protein forms, which are predicted to be inactivating. Experimental studies have shown that these mutations promote cancer cell proliferation, survival, and metastasis, partly due to aberrant localization of truncated proteins to the mitochondria, affecting genes involved in cell survival. This evidence supports a damaging effect of the TP53 Y327* variant.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 7.41
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Nonsense or frameshift variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351." The evidence for this variant shows: Y327* introduces a premature stop codon at amino acid 327, which is upstream of p.Lys351 and is predicted to trigger NMD. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant predicted to cause loss of function via NMD as per the VCEP decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but a different nucleotide change." The evidence for this variant shows: Y327* is a nonsense variant, not a missense variant yielding the same amino acid change. Therefore, this criterion is not applied because the variant does not meet the requirement of encoding the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo in a patient with the disease and no family history (with parental confirmation)." The evidence for this variant shows: No data on parental testing or de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 at Strong strength is: "Non-functional on Kato et al. data AND loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al.)." The evidence for this variant shows: Functional studies are general truncation assays not from Kato et al. or specified VCEP-approved assays. Therefore, this criterion is not applied because it does not meet the VCEP functional assay requirements.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is a points-based system: "Very Strong ≥8 points; Strong 4–7.5 points; Moderate 2–3.5 points; Supporting 1–1.5 points for proband observations with LFS-associated cancers." The evidence for this variant shows: No case-level or proband count data are provided. Therefore, this criterion is not applied due to absence of proband data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Missense variants within the following codons using transcript NM_000546.4: 175, 245, 248, 249, 273, 282 (or hotspots with ≥10 somatic occurrences)." The evidence for this variant shows: Y327* is a nonsense variant and not within these hotspot codons. Therefore, this criterion is not applied because it is not a missense hotspot variant.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large population database." The evidence for this variant shows: It is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent or below the frequency cutoff.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: No information on compound heterozygosity or recessive inheritance. Therefore, this criterion is not applied because PM3 is not relevant without recessive inheritance data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss." The evidence for this variant shows: This is a truncating variant covered by PVS1. Therefore, this criterion is not applied to avoid redundancy with PVS1.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic exist." The evidence for this variant shows: Y327* is a nonsense variant, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity and maternity." The evidence for this variant shows: No de novo or parental data. Therefore, this criterion is not applied due to absence of de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Cosegregation must be observed in ≥3–4 meioses for Supporting strength." The evidence for this variant shows: No family segregation data. Therefore, this criterion is not applied due to lack of segregation information.
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." The evidence for this variant shows: It is a nonsense variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Computational evidence of deleterious effect using specified algorithms (e.g., BayesDel, SpliceAI)." The evidence for this variant shows: Computational predictions are mixed or benign and PP3 cannot be used with PVS1. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Phenotype or family history highly specific for gene (e.g., LFS-associated phenotype)." The evidence for this variant shows: No phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available to perform independent evaluation." The evidence for this variant shows: ClinVar entries from two clinical laboratories classify Y327* as Pathogenic. Therefore, this criterion is applied at Supporting strength because of the reputable ClinVar submissions.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency (FAF) ≥0.001 in gnomAD continental subpopulations." The evidence for this variant shows: It is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filtering allele frequency (FAF) ≥0.0003 but <0.001 in gnomAD continental subpopulations." The evidence for this variant shows: It is absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "≥8 unrelated females age ≥60 without cancer." The evidence for this variant shows: No data on unaffected older individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 at Strong strength is: "Functional on Kato et al. data AND no loss of function on another assay." The evidence for this variant shows: Functional data indicate loss of function; no normal function data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "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 truncating variants are the primary mechanism of disease." The evidence for this variant shows: It 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 cis with a pathogenic variant." The evidence for this variant shows: No data on co-occurrence. 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 a repetitive region without known function." The evidence for this variant shows: It is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Computational evidence supports benign (BayesDel ≤ -0.008 and no predicted splicing impact)." The evidence for this variant shows: Not applicable for truncating variants and PP3/BP4 are not used with PVS1. 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 such reports. 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." The evidence for this variant shows: No benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous (silent) or intronic variant outside core splice sites with no predicted splicing impact." The evidence for this variant shows: It is a nonsense variant. Therefore, this criterion is not applied.