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TP53c.202G>TLikely pathogenic
Print report
Variant interpretation report

TP53 c.202G>T, p.(Glu68Ter)

NM_000546.5:c.202G>T NP_000537.3:p.(Glu68Ter) Nonsense · exon 4 View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

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.

NCBI Gene ↗ OncoKB ↗
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.
01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met, very strong: the exon 4 p.Glu68Ter stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions.

PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 observed allele frequency is 0, below the TP53 VCEP PM2 threshold of <0.00003.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) yields 9 points under the TP53 VCEP Version 2.4 point-based framework.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.181 maximum delta

Recorded SpliceAI maximum delta score: 0.181. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions

5 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
29 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52692559, n = 29 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 6 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For this exact TP53 nonsense variant, the available evidence does not provide the phenotype details or low-VAF observations required for TP53-specific PS4 or PP4.

PP5 and BP6 are not triggered because ClinVar contains no exact-variant Expert Panel classification; BP5 is not applicable under the TP53 VCEP framework.

PM3 and BP2 were adjudicated as not applicable because the governing TP53 VCEP Version 2.4 explicitly excludes both allelic criteria for TP53/Li-Fraumeni syndrome.

All three requested criteria are not_applicable because this variant is a truncating nonsense change, outside the consequence scope of PP3, BP4, and BP7.

SpliceAI, REVEL, and BayesDel values were not used to adjudicate these criteria because consequence scope is checked before predictor evaluation.

Population evidence supports PM2 at supporting strength because the variant is absent from the available gnomAD datasets.

BA1 and BS1 are not met because their TP53 VCEP ancestry-specific FAF thresholds are not reached.

BS2 remains unassessed because no qualifying unaffected older carrier cohort is documented.

Met · 2

PVS1 Very strongMet, very strong: the exon 4 p.Glu68Ter stop is upstream of p.Lys351 and outside TP53's exon 10/11 NMD escape regions. Details ▾Hide ▴
Reasoning

NM_000546.5:c.202G>T is a nonsense variant producing NP_000537.3:p.(Glu68Ter), with the premature termination codon in exon 4, upstream of p.Lys351. The TP53 VCEP PVS1 flowchart assigns full PVS1 to nonsense variants upstream of p.Lys351 when predicted to undergo NMD; its NMD exclusion regions are exon 11 and the 3'-most 50 nucleotides of exon 10, neither of which applies here. The ClinGen TP53 VCEP specification confirms this decision-tree rule and establishes loss of function as a disease mechanism for TP53. The exact variant was not listed in either governing PVS1 table, so the flowchart rule was applied to the documented consequence and exon context rather than a pre-assigned variant row.

Rule
TP53 VCEP PVS1 flowchart: nonsense upstream of p.Lys351 and predicted to undergo NMD = PVS1.
Evidence considered
  • 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.
Still missing
  • No exact c.202G>T, p.Glu68Ter, or p.E68* entry was found in PVS1-Flowchart.pdf.txt.
  • No exact c.202G>T, p.Glu68Ter, or p.E68* entry was found in PVS1-Splicing-Worksheet.xlsx.txt; this worksheet is for splice-site variants and is not applicable to this nonsense variant.
Sources
cspec ↗vcep_pvs1_flowchart
PM2 SupportingMet at supporting: gnomAD v4.1 observed allele frequency is 0, below the TP53 VCEP PM2 threshold of <0.00003. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP v2.4 specifies PM2 at supporting strength when the variant allele frequency is <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. The variant was absent from gnomAD v4.1 and gnomAD v2.1, and was also absent from the queried gnomAD v2.1 non-cancer and v3.1 non-cancer datasets. Therefore its observed allele frequency is 0 in the available population datasets and satisfies the VCEP PM2 threshold; no low-VAF allele-balance recalculation is indicated.

Rule
TP53 VCEP v2.4: Apply PM2 at supporting strength for an allele frequency <0.00003 in gnomAD or another large sequenced population; if multiple alleles are present within an ancestry group, that group's frequency must be <0.00004, excluding founder-effect groups.
Evidence considered
  • 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.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Not met · 4 · evaluated, threshold not reached

PP5 Not met: the exact ClinVar record has zero Expert Panel submissions, so its laboratory Pathogenic/Likely pathogenic labels cannot trigger PP5. Details ▾Hide ▴
Reasoning

PP5 is triggered here only by an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic. The exact ClinVar record for NM_000546.6(TP53):c.202G>T (p.Glu68Ter) has no Expert Panel submission and is reported through clinical laboratory submissions with criteria provided, so it does not satisfy the required Expert Panel source condition. The TP53 VCEP also states that PP5 is not for use.

Rule
Apply PP5 only for an exact-variant ClinVar Expert Panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions do not qualify.
Evidence considered
  • ClinVar submission audit: exact variant match, six clinical laboratory submissions, and zero Expert Panel submissions; classifications are Pathogenic or Likely pathogenic from non-expert submissions.
  • The TP53 VCEP specifies that PP5 is not for use, and no exact-variant Expert Panel classification was identified.
Sources
clinvar ↗cspec ↗
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. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP v2.4 requires a gnomAD continental-subpopulation filtering allele frequency (FAF) of >=0.001 in one non-founder genetic ancestry group, with >=2,000 alleles tested and at least 2 variant alleles, for BA1. The variant was absent from gnomAD v4.1 and gnomAD v2.1, so no population FAF reaches the BA1 threshold. The VCEP's most recent-population-data preference supports using gnomAD v4.1 as the default; the available non-cancer searches were also absent.

Rule
TP53 VCEP v2.4: Filtering allele frequency (FAF) of >= 0.001 in a gnomAD continental subpopulation of a single eligible genetic ancestry group; group must have >=2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
  • TP53 VCEP v2.4 BA1 rule: FAF >=0.001 in a single eligible continental genetic ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v4.1 reports the variant as absent; 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.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
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. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP v2.4 requires a gnomAD continental-subpopulation FAF of >=0.0003 but <0.001 in one non-founder genetic ancestry group, with >=2,000 alleles tested and at least 2 variant alleles, for BS1. The variant was absent from gnomAD v4.1 and gnomAD v2.1, so no population FAF meets the BS1 threshold. The available non-cancer searches were also absent, and there is no allele-balance signal requiring a CHIP recalculation.

Rule
TP53 VCEP v2.4: Filtering allele frequency (FAF) of >= 0.0003 but < 0.001 in a gnomAD continental subpopulation of a single eligible genetic ancestry group; group must have >=2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
  • TP53 VCEP v2.4 BS1 rule: FAF >=0.0003 but <0.001 in a single eligible continental genetic ancestry group, with >=2,000 alleles tested and at least 2 variant alleles.
  • gnomAD v4.1 reports the variant as absent; 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.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
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. Details ▾Hide ▴
Reasoning

BP6 is triggered here only by an exact-variant ClinVar Expert Panel classification of Benign or Likely benign. The exact ClinVar record has zero Expert Panel submissions and contains only non-expert clinical laboratory classifications of Pathogenic or Likely pathogenic, with no benign assertion. Therefore BP6 is not met. The TP53 VCEP also states that BP6 is not for use.

Rule
Apply BP6 only for an exact-variant ClinVar Expert Panel Benign or Likely benign classification; ordinary laboratory submissions do not qualify.
Evidence considered
  • ClinVar submission audit: exact variant match, zero Expert Panel submissions, and no Benign or Likely benign submission; the recorded laboratory classifications are Pathogenic or Likely pathogenic.
  • The TP53 VCEP specifies that BP6 is not for use.
Sources
clinvar ↗cspec ↗

Not assessed · 6 · no assessment recorded

PS2 Not assessed: no documented de novo proband, parental testing, or maternity/paternity confirmation is available to assign PS2 points under the VCEP thresholds. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PS2 exclusively for de novo evidence and requires tallying confirmed de novo probands by cancer type and maternity/paternity status: 1 point is Supporting, 2-3 Moderate, 4-7 Strong, and at least 8 Very Strong. The available case evidence contains no documented proband phenotype, parental testing, maternity or paternity confirmation, family history, or de novo observation for NM_000546.5:c.202G>T (p.Glu68Ter; p.E68*), so no PS2 points can be assigned. The governing VCEP table was searched for all three variant notations, but it is a general cancer-points table and contains no variant-specific entry.

Rule
TP53 VCEP PS2: de novo points are tallied by proband cancer type and confirmed maternity/paternity; Supporting = 1 point, Moderate = 2-3 points, Strong = 4-7 points, Very Strong = >=8 points.
Evidence considered
  • The TP53 VCEP Version 2.4 rule states that de novo points are tallied by confirmed maternity/paternity and proband cancer type, with PS2 Supporting at 1 point, Moderate at 2-3 points, Strong at 4-7 points, and Very Strong at at least 8 points.
  • The TP53 VCEP explicitly states that PM6 is dropped and PS2 is used exclusively for de novo evidence.
  • The case bundle and directly reviewed prefetch material provide no case-specific proband, parental, maternity, paternity, family-history, or de novo data for this variant.
Still missing
  • No documented proband cancer phenotype or LFS-associated cancer type/age is available.
  • No parental testing or confirmation of maternity and paternity is available.
  • No family-history information is available to establish de novo status.
  • No c.202G>T, p.Glu68Ter, or p.E68* entry was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt; the searched file provides general cancer categories and PS2 point thresholds rather than variant-specific observations.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
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. Details ▾Hide ▴
Reasoning

The TP53 VCEP specifies PS4 point scoring from proband-level Revised Chompret criteria (0.5 point), Classic LFS criteria (1 point), or HER2-positive breast cancer diagnosed below age 40 (0.5 point), with PS4 Supporting at 1-1.5 points, Moderate at 2-3.5 points, Strong at 4-7.5 points, and Very Strong at >=8 points. The available exact-variant ClinVar record supplies only a bilateral breast cancer condition label and does not establish the proband's age, HER2 status, Revised Chompret criteria, Classic LFS criteria, or the required exclusion conditions. No exact-variant case-control odds ratio or qualifying multi-proband phenotype dataset was identified. The searched PS4-Points-Table.pdf.txt contains no entry for c.202G>T, p.Glu68Ter, or p.E68*; therefore no pre-assigned variant-specific PS4 code overrides the VCEP scoring framework. PS4 cannot be assigned without phenotype details or qualifying case-control evidence.

Rule
TP53 VCEP PS4: Revised Chompret = 0.5 point; Classic LFS = 1 point; HER2-positive breast cancer below age 40 = 0.5 point; PS4 Supporting = 1-1.5 points, Moderate = 2-3.5 points, Strong = 4-7.5 points, Very Strong >=8 points.
Evidence considered
  • The TP53 VCEP PS4 rule assigns 0.5 point for Revised Chompret criteria, 1 point for Classic LFS criteria, and 0.5 point for unrelated probands with HER2-positive breast cancer diagnosed below age 40; strengths are Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, and Very Strong >=8 points.
  • The exact ClinVar variant record is NM_000546.6(TP53):c.202G>T (p.Glu68Ter) and lists bilateral breast cancer, but it does not provide the age, HER2 status, or criteria needed to calculate TP53 VCEP PS4 points.
  • The searched PS4-Points-Table.pdf.txt had no exact-variant entry for c.202G>T, p.Glu68Ter, or p.E68*; the generic VCEP point table therefore remains governing.
Still missing
  • No proband age at breast cancer diagnosis or age-based Revised Chompret/Classic LFS assessment.
  • No HER2 status for the reported breast cancer.
  • No documented qualifying PS4 case-control odds ratio with confidence interval.
  • PS4-Points-Table.pdf.txt was searched for c.202G>T, p.Glu68Ter, and p.E68*; no entry for this variant was found.
Sources
cspec ↗vcep_ps4_points_tableclinvar ↗PMID:26845104 ↗PMID:30224644 ↗
PP1 Not assessed: no variant-positive affected relatives, obligate carriers, or counted meioses are documented for comparison with the 3-4 meiosis PP1 threshold. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires PP1 meioses to involve individuals who both carry the variant and have a relevant LFS-associated cancer, with unaffected obligate carriers also potentially contributing meioses. Cosegregation is Supporting for 3-4 meioses, Moderate for 5-6, and Strong for at least 7 meioses across more than one family. No affected relatives, variant-positive relatives, obligate carriers, family structure, or meiosis count is documented for NM_000546.5:c.202G>T (p.Glu68Ter; p.E68*), so PP1 cannot be assigned. The governing VCEP table was searched for all three variant notations, but it contains no variant-specific entry.

Rule
TP53 VCEP PP1: Supporting = 3-4 cosegregating meioses, Moderate = 5-6, Strong = >=7 across >1 family; meioses require variant carriage and relevant LFS cancer, with limited exceptions for obligate carriers and qualifying tumor-only observations.
Evidence considered
  • The TP53 VCEP PP1 rule counts meioses among variant carriers with relevant LFS-associated cancer, allows meioses through unaffected obligate carriers, and assigns Supporting at 3-4, Moderate at 5-6, and Strong at at least 7 meioses across more than one family.
  • The case bundle and directly reviewed prefetch material provide no family segregation data, relative genotypes, affected-relative phenotypes, obligate carriers, or meiosis count for this variant.
Still missing
  • No family pedigree or list of informative relatives is available.
  • No germline variant testing results for affected relatives or obligate carriers are available.
  • No relevant LFS-associated cancers, ages, or meioses are documented.
  • No c.202G>T, p.Glu68Ter, or p.E68* entry was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt; the searched file provides general LFS cancer categories and PP1-related context rather than variant-specific segregation observations.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 Not assessed: TP53 PP4 requires qualifying low-VAF observations, but no VAF or independent low-VAF evidence is available for this variant. Details ▾Hide ▴
Reasoning

The TP53 VCEP PP4 rule is a low-variant-allele-fraction somatic/constitutional-mosaicism rule, not a general phenotype-specificity rule: Supporting requires one observation with VAF 5-35%, and Moderate requires at least two independent observations with VAF 5-25%, with additional VCEP caveats. The case materials provide no VAF, blood/tissue source, or independent low-VAF observations for this exact variant. The bilateral breast cancer condition label alone cannot satisfy the VCEP PP4 rule.

Rule
TP53 VCEP PP4: Moderate requires at least 2 independent observations with VAF 5-25%; Supporting requires observation with VAF 5-35%, subject to VCEP somatic-origin and exclusion caveats.
Evidence considered
  • The TP53 VCEP PP4 rule requires at least two independent observations at VAF 5-25% for Moderate or an observation at VAF 5-35% for Supporting, with specific caveats for presumed somatic or constitutional mosaicism.
  • The exact ClinVar record provides a bilateral breast cancer condition label but no VAF or qualifying independent low-VAF observations.
Still missing
  • No variant allele fraction is reported for the exact variant.
  • No blood/tissue source or independent-observation count is reported.
Sources
cspec ↗clinvar ↗
BS2 Not assessed: no qualifying unaffected female carriers aged >=60 from a single documented source were available for the TP53 BS2 rule. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP v2.4 BS2 rule requires observations of at least 2 unrelated females aged >=60 years without cancer from one source for supporting strength, 4-7 for moderate strength, or >=8 for strong strength, with older individuals diagnosed with sarcoma excluded. The available case evidence contains no qualifying unaffected-female carrier observations, ages, cancer status, or single-source cohort documentation, so BS2 cannot be assessed.

Rule
TP53 VCEP v2.4: >=8 unrelated females aged >=60 years without cancer from one source = BS2_Strong; 4-7 = BS2_Moderate; 2-3 = BS2_Supporting. Exclude individuals with sarcoma diagnosed at >=61 years.
Evidence considered
  • TP53 VCEP v2.4 BS2 rule requires unrelated females aged >=60 years without cancer from a single source: 2-3 for supporting, 4-7 for moderate, or >=8 for strong.
  • No qualifying unaffected-female carrier observations or source-level cohort details were present in the available case evidence.
Still missing
  • Qualifying unaffected female carrier count, ages, cancer status, and single-source provenance are unavailable.
Sources
cspec ↗
BS4 Not assessed: no affected relatives with documented absence of the variant are available to establish lack of segregation for BS4. Details ▾Hide ▴
Reasoning

The TP53 VCEP permits BS4 Strong for lack of segregation in affected family members diagnosed with LFS-associated cancers listed in its PS2/PP1 cancer table, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. No affected family members, their variant results, family pedigree, or non-segregation observations are documented for NM_000546.5:c.202G>T (p.Glu68Ter; p.E68*), so BS4 cannot be assessed. The governing VCEP table was searched for all three variant notations, but it contains no variant-specific entry.

Rule
TP53 VCEP BS4 Strong: lack of segregation in affected family members diagnosed with LFS-associated cancers listed in the PS2/PP1 cancer table.
Evidence considered
  • The TP53 VCEP BS4 rule applies Strong evidence for lack of segregation in affected family members diagnosed with LFS-associated cancers listed in the VCEP cancer table and warns about phenocopies and multiple pathogenic variants.
  • The case bundle and directly reviewed prefetch material provide no affected-relative genotypes, family pedigree, or non-segregation observation for this variant.
Still missing
  • No affected family members or LFS-associated cancer diagnoses are documented.
  • No genotype results for affected relatives are available to demonstrate absence of the variant.
  • No pedigree information is available to evaluate phenocopies or an alternative pathogenic variant.
  • No c.202G>T, p.Glu68Ter, or p.E68* entry was found in Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt; the searched file provides general LFS cancer categories rather than variant-specific non-segregation observations.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the variant is nonsense, p.Glu68Ter, and no alternate nucleotide change producing the same amino-acid consequence is documented. Details ▾Hide ▴
Reasoning

The TP53 VCEP permits PS1 only for a variant with the same amino-acid change as a variant asserted pathogenic or likely pathogenic under the VCEP specifications. This case variant is the nonsense change NM_000546.5:c.202G>T, p.(Glu68Ter), not a missense substitution, and no separately documented alternate nucleotide change producing the same p.Glu68Ter consequence is available in the reviewed evidence.

Rule
Can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications; Moderate can be applied to variants asserted as Likely Pathogenic following the TP53 VCEP’s specifications.
Evidence considered
  • The TP53 VCEP PS1 rule allows PS1 for variants asserted pathogenic or likely pathogenic following TP53 VCEP specifications.
  • Variant normalization identifies NM_000546.5:c.202G>T as the nonsense consequence NP_000537.3:p.(Glu68Ter).
  • No separately documented alternate nucleotide change producing p.Glu68Ter was identified among the reviewed case evidence.
Sources
cspec ↗
PS3 N/ANot applicable: TP53 VCEP PS3 covers missense or small in-frame deletions, whereas c.202G>T is a nonsense p.(Glu68Ter) variant with no exact worksheet entry. Details ▾Hide ▴
Reasoning

The TP53 VCEP functional specification limits PS3 assessment to missense variants and small in-frame deletions. NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), so the governing functional code framework does not apply. The Functional-worksheet.xlsx was searched for c.202G>T, p.Glu68Ter, and p.E68*; no exact entry was found. The eligible functional literature extraction for PMID:30224644 describes position-dependent stop-codon screening but does not mention this exact variant and cannot supply a variant-specific PS3 assignment.

Rule
TP53 VCEP functional rules apply to missense variants and small in-frame deletions; PS3 is not applicable to this nonsense variant.
Evidence considered
  • The TP53 VCEP functional flowchart defines PS3/BS3 application for missense variants and small in-frame deletions.
  • The case normalization identifies NM_000546.5:c.202G>T as a nonsense variant producing NP_000537.3:p.(Glu68Ter), also represented as p.(E68*).
  • Functional-worksheet.xlsx was searched under c.202G>T, p.Glu68Ter, and p.E68*; no exact row was found.
  • PMID:30224644 reports a comprehensive TP53 stop-codon screen with different patterns across codon intervals, but does not explicitly mention c.202G>T or p.(E68*) and provides no variant-specific PS3 result.
Still missing
  • No exact c.202G>T, p.Glu68Ter, or p.E68* entry was found in Functional-worksheet.xlsx.
  • No variant-specific PS3 functional assignment was identified in the consulted functional literature extraction for PMID:30224644.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:30224644 ↗
PM1 N/ANot applicable: p.Glu68Ter is a nonsense variant at codon 68, outside the TP53 VCEP’s specified missense codons 175, 245, 248, 249, 273, and 282. Details ▾Hide ▴
Reasoning

The TP53 VCEP PM1 rule applies to missense variants at codons 175, 245, 248, 249, 273, or 282, or to qualifying Cancer Hotspots same-amino-acid observations. The case variant is a nonsense variant at codon 68 (p.Glu68Ter), and the authoritative vcep_materials.json domain_tables object is empty; therefore no PM1 domain or hotspot rule applies.

Rule
Missense variants within codons 175, 245, 248, 249, 273, or 282; alternatively, germline missense variants seen in cancerhotspots.org with at least 10 somatic occurrences for the same amino acid change may receive Moderate, while 2–9 same-amino-acid occurrences may receive Supporting.
Evidence considered
  • The TP53 VCEP PM1 rule specifies missense variants at codons 175, 245, 248, 249, 273, and 282, with an alternate hotspot provision for qualifying same-amino-acid missense observations.
  • The normalized consequence is nonsense p.(Glu68Ter), corresponding to codon 68 rather than a specified PM1 codon.
  • The authoritative vcep_materials.json domain_tables key contains no TP53 entry, and the collected hotspot result reports no statistically significant hotspot for TP53 E68.
Sources
cspec ↗vcep_hotspots_vision_instruction
PM3 VCEPNot applicable: the TP53 VCEP Version 2.4 explicitly excludes PM3 because Li-Fraumeni syndrome is autosomal dominant. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP Version 2.4 specification explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome. TP53/Li-Fraumeni syndrome is governed as an autosomal-dominant condition, so recessive-disease evidence for a pathogenic variant in trans is not applicable. The available case evidence does not establish any PM3-type biallelic or phase observation, but this does not alter the VCEP-defined inapplicability.

VCEP rule
This rule does not apply to TP53/Li-Fraumeni syndrome.
Evidence considered
  • The governing ClinGen TP53 VCEP Version 2.4 specification states: "This rule does not apply to TP53/Li-Fraumeni syndrome."
  • The TP53 framework identifies Li-Fraumeni syndrome as autosomal dominant, making the recessive-disease PM3 model inapplicable.
  • No case-specific biallelic, in-trans, or parental-phase observation was documented in the reviewed evidence.
Sources
cspec ↗
PM4 VCEPNot applicable: TP53 VCEP Version 2.4 explicitly excludes PM4, and this variant is a nonsense loss-of-function allele. Details ▾Hide ▴
Reasoning

PM4 is explicitly marked Not Applicable in the ClinGen TP53 Expert Panel Version 2.4 specification. This variant is a nonsense loss-of-function allele, not an in-frame protein-length change or an extension/deletion category for which PM4 would be evaluated.

VCEP rule
TP53 VCEP Version 2.4: PM4 not applicable.
Evidence considered
  • The ClinGen TP53 Expert Panel Version 2.4 specification lists PM4 as Not Applicable.
  • The variant consequence is nonsense, p.(Glu68Ter), rather than an in-frame deletion, insertion, or protein-extension event.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires a missense variant, whereas this case variant is the nonsense consequence p.Glu68Ter. Details ▾Hide ▴
Reasoning

The TP53 VCEP PM5 rule requires a missense variant at an amino-acid residue where one or more different missense variants have previously been determined pathogenic or likely pathogenic under the TP53 specifications. This case variant is the nonsense change p.(Glu68Ter), so same-residue missense PM5 does not apply.

Rule
Missense variant at an amino-acid residue where at least 2 different missense variants previously determined pathogenic supports Strong; 1 pathogenic missense variant supports Moderate; 1 clinically supported likely pathogenic missense variant supports Supporting.
Evidence considered
  • The TP53 VCEP PM5 rule is restricted to missense variants and counts qualifying different missense variants at the same amino-acid residue.
  • Variant normalization identifies p.(Glu68Ter), a nonsense consequence rather than a missense consequence.
  • The collected PM5 candidate summary marks classic same-residue missense searching inapplicable because the variant consequence is nonsense.
Sources
cspec ↗pm5_candidates
PM6 VCEPNot applicable: the TP53 VCEP dropped PM6 and requires all de novo evidence to be evaluated through PS2. Details ▾Hide ▴
Reasoning

PM6 is not applicable under the TP53 VCEP Version 2.4 framework. The VCEP explicitly states that it has dropped PM6 and uses PS2 exclusively for de novo evidence; assumed de novo observations without confirmed maternity and paternity therefore cannot be assigned PM6 in this framework.

VCEP rule
TP53 VCEP PM6: not applicable; see the combined PS2/PM6 rule, which directs all de novo evidence to PS2 exclusively.
Evidence considered
  • The TP53 VCEP Version 2.4 PS2 instructions state that PM6 is dropped and PS2 is used exclusively for de novo evidence.
Sources
cspec ↗
PP2 VCEPNot applicable: the TP53 VCEP designates PP2 as not applicable, and this variant is nonsense rather than missense. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly designates PP2 as not applicable. In addition, this variant is nonsense rather than a missense variant for which the generic PP2 concept would ordinarily be considered.

VCEP rule
Not Applicable under the TP53 VCEP specification.
Evidence considered
  • The governing TP53 VCEP specification lists PP2 as Not Applicable.
  • Variant normalization identifies the consequence as p.(Glu68Ter), a nonsense variant.
Sources
cspec ↗
PP3 N/ANot applicable: the variant is a nonsense change, so TP53 computational PP3 is outside scope regardless of the available SpliceAI or BayesDel values. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), and the governing TP53 computational specification limits PP3 to missense, splice-region, intronic, synonymous, or specified in-frame-deletion/splice-effect contexts; truncating variants are outside this criterion's scope. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in the governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf, PP3-BP4-codes.xlsx, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx materials, but those lookup results do not alter the upstream consequence-based exclusion.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP computational materials govern PP3 for missense and specified splice-related/in-frame contexts, not truncating nonsense variants.
  • The three governing searchable VCEP files were checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in PP3-BP4-codes.xlsx.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BS3 N/ANot applicable: TP53 VCEP BS3 covers missense or small in-frame deletions, whereas c.202G>T is a nonsense p.(Glu68Ter) variant with no exact worksheet entry. Details ▾Hide ▴
Reasoning

The TP53 VCEP functional specification limits BS3 assessment to missense variants and small in-frame deletions. NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), so the governing functional code framework does not apply. The Functional-worksheet.xlsx was searched for c.202G>T, p.Glu68Ter, and p.E68*; no exact entry was found. The eligible functional literature extraction for PMID:30224644 describes position-dependent stop-codon screening but does not mention this exact variant and cannot supply a variant-specific BS3 assignment.

Rule
TP53 VCEP functional rules apply to missense variants and small in-frame deletions; BS3 is not applicable to this nonsense variant.
Evidence considered
  • The TP53 VCEP functional flowchart defines PS3/BS3 application for missense variants and small in-frame deletions.
  • The case normalization identifies NM_000546.5:c.202G>T as a nonsense variant producing NP_000537.3:p.(Glu68Ter), also represented as p.(E68*).
  • Functional-worksheet.xlsx was searched under c.202G>T, p.Glu68Ter, and p.E68*; no exact row was found.
  • PMID:30224644 reports a comprehensive TP53 stop-codon screen with different patterns across codon intervals, but does not explicitly mention c.202G>T or p.(E68*) and provides no variant-specific BS3 result.
Still missing
  • No exact c.202G>T, p.Glu68Ter, or p.E68* entry was found in Functional-worksheet.xlsx.
  • No variant-specific BS3 functional assignment was identified in the consulted functional literature extraction for PMID:30224644.
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:30224644 ↗
BP1 VCEPNot applicable: the TP53 VCEP designates BP1 as not applicable, and this variant is nonsense rather than missense. Details ▾Hide ▴
Reasoning

The TP53 VCEP explicitly designates BP1 as not applicable. The variant is also nonsense, not a missense variant to which the generic BP1 concept would ordinarily apply.

VCEP rule
Not Applicable under the TP53 VCEP specification.
Evidence considered
  • The governing TP53 VCEP specification lists BP1 as Not Applicable.
  • Variant normalization identifies the consequence as p.(Glu68Ter), a nonsense variant.
Sources
cspec ↗
BP2 VCEPNot applicable: the TP53 VCEP Version 2.4 marks BP2 not applicable, regardless of its phase-confirmed trans or three-observation framework. Details ▾Hide ▴
Reasoning

The ClinGen TP53 VCEP Version 2.4 specification marks BP2 as not applicable for TP53. Although the specification describes a benign framework based on a phase-confirmed trans observation with a pathogenic or likely pathogenic TP53 variant, or at least three observations with at least two different pathogenic or likely pathogenic TP53 variants when phase is unknown, no such case-specific allelic observations are documented here. The governing VCEP inapplicability controls the adjudication.

VCEP rule
Evidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic or likely pathogenic TP53 variants.
Evidence considered
  • The governing ClinGen TP53 VCEP Version 2.4 specification lists BP2 as not applicable for TP53.
  • The specification describes BP2 as requiring either a phase-confirmed trans observation with a pathogenic or likely pathogenic TP53 variant, or at least three observations involving at least two different pathogenic or likely pathogenic TP53 variants when phase is unknown.
  • The reviewed case evidence contains no documented cis/trans phase, affected-proband allelic observation, or qualifying pathogenic-variant co-observation.
Sources
cspec ↗
BP3 VCEPNot applicable: TP53 VCEP Version 2.4 explicitly excludes BP3, and p.Glu68Ter is a premature-stop variant rather than an in-frame repeat-region deletion. Details ▾Hide ▴
Reasoning

BP3 is explicitly marked Not Applicable in the ClinGen TP53 Expert Panel Version 2.4 specification. The variant is a nonsense change producing a premature termination codon, not an in-frame deletion in a repetitive region without functional impact.

VCEP rule
TP53 VCEP Version 2.4: BP3 not applicable.
Evidence considered
  • The ClinGen TP53 Expert Panel Version 2.4 specification lists BP3 as Not Applicable.
  • The variant consequence is nonsense, p.(Glu68Ter), so the benign in-frame deletion-in-repeat-region rule does not apply.
Sources
cspec ↗
BP4 N/ANot applicable: the variant is a nonsense change, so TP53 computational BP4 is outside scope regardless of the available SpliceAI or BayesDel values. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), and the governing TP53 computational specification limits BP4 to missense, splice-region, intronic, synonymous, or specified in-frame-deletion/splice-effect contexts; truncating variants are outside this criterion's scope. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in the governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf, PP3-BP4-codes.xlsx, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx materials, but those lookup results do not alter the upstream consequence-based exclusion.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP computational materials govern BP4 for missense and specified splice-related/in-frame contexts, not truncating nonsense variants.
  • The three governing searchable VCEP files were checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in PP3-BP4-codes.xlsx.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5 VCEPNot applicable: the TP53 VCEP designates BP5 as not applicable and provides no case-specific benign alternative diagnosis. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP5 as not applicable. No governing TP53 BP5 rule is available for this case, and no benign alternative molecular diagnosis or phenotype-discordant finding was supplied that could override the gene-specific designation.

VCEP rule
TP53 VCEP BP5: Not applicable.
Evidence considered
  • The TP53 VCEP framework lists BP5 as not applicable.
Sources
cspec ↗
BP7 N/ANot applicable: the variant is nonsense rather than synonymous or intronic, so TP53 BP7 cannot be applied. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), not a synonymous variant. BP7 is restricted by the TP53 VCEP specification to synonymous or qualifying intronic variants, so SpliceAI is not evaluated for BP7 in this case. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP BP7 rule is limited to synonymous or qualifying intronic variants.
  • The governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf was checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Identifiers

Gene
TP53
Transcript
NM_000546.5
Coding (HGVS c.)
NM_000546.5:c.202G>T
Protein (HGVS p.)
NP_000537.3:p.(Glu68Ter)
GRCh38
chr17:7676167 C>A
GRCh37
chr17:7579485 C>A
Location and type
Exon 4 · nonsense
ClinVar
224551
COSMIC
COSV52692559

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.

TP53NM_000546.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +86 bp
0.009
SpliceAI acceptor gainat -99 bp
0.090
SpliceAI donor lossat -173 bp
0.015
SpliceAI donor gainat +27 bp
0.181
Pangolin splice lossmagnitude shown
-0.074
Pangolin splice gain
0.086

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/ANot applicable: the variant is a nonsense change, so TP53 computational PP3 is outside scope regardless of the available SpliceAI or BayesDel values. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), and the governing TP53 computational specification limits PP3 to missense, splice-region, intronic, synonymous, or specified in-frame-deletion/splice-effect contexts; truncating variants are outside this criterion's scope. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in the governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf, PP3-BP4-codes.xlsx, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx materials, but those lookup results do not alter the upstream consequence-based exclusion.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP computational materials govern PP3 for missense and specified splice-related/in-frame contexts, not truncating nonsense variants.
  • The three governing searchable VCEP files were checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in PP3-BP4-codes.xlsx.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP4 N/ANot applicable: the variant is a nonsense change, so TP53 computational BP4 is outside scope regardless of the available SpliceAI or BayesDel values. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), and the governing TP53 computational specification limits BP4 to missense, splice-region, intronic, synonymous, or specified in-frame-deletion/splice-effect contexts; truncating variants are outside this criterion's scope. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in the governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf, PP3-BP4-codes.xlsx, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx materials, but those lookup results do not alter the upstream consequence-based exclusion.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP computational materials govern BP4 for missense and specified splice-related/in-frame contexts, not truncating nonsense variants.
  • The three governing searchable VCEP files were checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in PP3-BP4-codes.xlsx.
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP7 N/ANot applicable: the variant is nonsense rather than synonymous or intronic, so TP53 BP7 cannot be applied. Details ▾Hide ▴
Reasoning

Not applicable: NM_000546.5:c.202G>T is a nonsense variant producing p.(Glu68Ter)/p.(E68*), not a synonymous variant. BP7 is restricted by the TP53 VCEP specification to synonymous or qualifying intronic variants, so SpliceAI is not evaluated for BP7 in this case. No entry for c.202G>T, p.Glu68Ter, or p.E68* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.

Evidence considered
  • The case normalization identifies NM_000546.5:c.202G>T as the nonsense consequence p.(Glu68Ter), also written p.(E68*).
  • The TP53 VCEP BP7 rule is limited to synonymous or qualifying intronic variants.
  • The governing Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf was checked under c.202G>T, p.Glu68Ter, and p.E68*; no exact variant entry was found.
Still missing
  • No entry for c.202G>T, p.Glu68Ter, or p.E68* in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18). BayesDel score = 0.66.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
    No paper-specific finding is recorded.
    PMID 11753428 ↗
  • Rescuing the function of mutant p53.
    No paper-specific finding is recorded.
    PMID 11900253 ↗
  • The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.
    No paper-specific finding is recorded.
    PMID 16007150 ↗
  • High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
    No paper-specific finding is recorded.
    PMID 19336573 ↗
  • Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
    No paper-specific finding is recorded.
    PMID 21467160 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Improving performance of multigene panels for genomic analysis of cancer predisposition.
    Shirts BH et al. · 2016
    This study evaluated germline variants in 1,462 patients tested with the BROCA or ColoSeq multigene panels and reported five total damaging TP53 mutations across the cohort, but it does not provide a variant-level observation, phenotype, segregation result, or case-control estimate for TP53 c.202G>T (p.E68*).
    Does not name this variant
    PMID 26845104 ↗
    Quoted passage
    Of 1,462 patients, 179 (12.2%) carried a pathogenic or likely pathogenic mutation in a known cancer gene.

    Results, Positive results; Table 2, Total damaging mutations in gene

  • Mutational processes shape the landscape of TP53 mutations in human cancer.
    Giacomelli AO et al. · 2018
    The paper describes a comprehensive TP53 mutagenesis screen that included stop-codon substitutions at every codon and reports position-dependent functional patterns, but it does not explicitly mention TP53 c.202G>T or p.(E68*).
    Does not name this variant
    PMID 30224644 ↗
    Quoted passage
    We also found that not all alleles bearing stop codon mutations behaved as LOF alleles, with different patterns observed for stop codons at positions 1–43, 44–289, 290–362, and 363–393 (Fig. 2b–d, Supplementary Fig. 4–5).

    Results, TP53-MITE enrichment screens, paragraph discussing stop-codon alleles

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.181 Open source ↗
ClinVar 5 Pathogenic · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 224551)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18). BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52692559, n = 29 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.