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NM_000546.5:c.202G>T
p.Glu68Ter · TP53
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 · v2.4
0%
complete
Final classification
Likely Pathogenic
PVS1PM2
TP53
c.202G>T
p.Glu68Ter
nonsense · exon 4
Gene context NCBI Gene ↗ OncoKB ↗

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

This variant

TP53 encodes the p53 tumor suppressor that protects against damaged cells through cell-cycle arrest, DNA repair, senescence, and apoptosis; inherited pathogenic TP53 variants cause Li-Fraumeni syndrome with a high risk of early-onset multiple cancers.

Transcript
NM_000546.5
HGVS · transcript:coding
NM_000546.5:c.202G>T
GRCh38
chr17:7676167 C>A
GRCh37
chr17:7579485 C>A
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) yields 9 points under the TP53 VCEP Version 2.4 point-based framework.
Classification rationale
PVS1PM2 Likely Pathogenic
TP53 c.202G>T nonsense · exon 4

PVS1 very strong: the exon 4 p.Glu68Ter premature stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions. PM2 supporting: the variant is absent from gnomAD v4.1, with an observed allele frequency of 0 below the TP53 VCEP threshold.

PVS1 + PM2 → Likely Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_000546.5 · variants mapped to exon structure
TP53 NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met, very strong: the exon 4 p.Glu68Ter stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions.
The case evidence identifies NM_000546.5:c.202G>T as NP_000537.3:p.(Glu68Ter) / p.(E68*) and places the variant in exon 4.The TP53 VCEP PVS1 flowchart states that nonsense variants upstream of p.Lys351 predicted to undergo NMD receive PVS1; exon 11 and the 3'-most 50 nucleotides of exon 10 are the specified NMD exceptions.The ClinGen TP53 VCEP Version 2.4 specification identifies the PVS1 default as Pathogenic Very Strong and directs use of the TP53 PVS1 decision tree.
cspec ↗
PM2 supporting Pathogenic
Met at supporting: gnomAD v4.1 observed allele frequency is 0, below the TP53 VCEP PM2 threshold of <0.00003.
TP53 VCEP v2.4 PM2 rule: allele frequency <0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's frequency must be <0.00004, excluding founder-effect groups.gnomAD v4.1 reports the variant as absent, corresponding to an observed allele frequency of 0; gnomAD v2.1 also reports it as absent.The queried gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer datasets also report the variant as absent.
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
Assessed · not applied · 4 not met · 6 not assessed
Pathogenic
PS2 Not assessed: no documented de novo proband, parental testing, or maternity/paternity confirmation is available to assign PS2 points under the VCEP thresholds.
PS4 Not assessed: ClinVar records bilateral breast cancer, but age, HER2 status, LFS criteria, and qualifying case-control enrichment needed for TP53 PS4 are unavailable.
PP1 Not assessed: no variant-positive affected relatives, obligate carriers, or counted meioses are documented for comparison with the 3-4 meiosis PP1 threshold.
PP4 Not assessed: TP53 PP4 requires qualifying low-VAF observations, but no VAF or independent low-VAF evidence is available for this variant.
PP5 Not met: the exact ClinVar record has zero Expert Panel submissions, so its laboratory Pathogenic/Likely pathogenic labels cannot trigger PP5.
Benign
BA1 Not met: the variant was absent from gnomAD v4.1, far below the TP53 VCEP BA1 threshold of FAF >=0.001 in one eligible ancestry group.
BS1 Not met: the variant was absent from gnomAD v4.1, below the TP53 VCEP BS1 threshold of FAF >=0.0003 in one eligible ancestry group.
BS2 Not assessed: no qualifying unaffected female carriers aged >=60 from a single documented source were available for the TP53 BS2 rule.
BS4 Not assessed: no affected relatives with documented absence of the variant are available to establish lack of segregation for BS4.
BP6 Not met: no exact-variant ClinVar Expert Panel Benign or Likely benign classification exists, and all usable laboratory assertions are pathogenic or likely pathogenic.
N/A · 16 PS1 · PS3 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP3 · BP4 · BP5 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 224551)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18). BayesDel score = 0.66.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52692559, n = 29 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
11753428 ↗ A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. ONCOKB
11900253 ↗ Rescuing the function of mutant p53. ONCOKB
16007150 ↗ The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. ONCOKB
19336573 ↗ High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. ONCOKB
21467160 ↗ Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma. ONCOKB
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
26845104 ↗ Improving performance of multigene panels for genomic analysis of cancer predisposition. CLINVAR
30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer. CLINVAR