About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.267del, p.(Ser90ProfsTer33)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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 v2.4.0. 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
This frameshift variant, NM_000546.6:c.267del (p.Ser90ProfsTer33), introduces a premature termination codon at codon 122, well upstream of the TP53 VCEP p.Lys351 cutoff for nonsense-mediated decay; under the TP53 PVS1 flowchart, a frameshift-induced premature stop predicted to undergo nonsense-mediated decay supports PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; an observed allele frequency of 0 is below the TP53 VCEP PM2 threshold of less than 0.00003.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
2 Pathogenic · 1 Likely pathogenic.
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
30 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52685476, n = 30 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 6 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The TP53 c.267del (p.Ser90ProfsTer33) variant has been observed in somatic cancers in COSMIC (30 occurrences) and has been reported in ClinVar with Pathogenic and Likely pathogenic germline submissions.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, placing its allele frequency below the TP53 PM2 threshold of less than 0.00003.
This early frameshift creates a premature stop at codon 122, which is well upstream of the TP53 VCEP p.Lys351 cutoff for predicted nonsense-mediated decay and supports PVS1 at very strong strength.
SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), and this does not weaken the TP53 null-variant interpretation.
No criteria match.
Met · 2
PVS1 Very strongThis frameshift variant, NM_000546.6:c.267del (p.Ser90ProfsTer33), introduces a premature termination codon at codon 122, well upstream of the TP53 VCEP p.Lys351 cutoff for nonsense-mediated decay; under the TP53 PVS1 flowchart, a frameshift-induced premature stop predicted to undergo nonsense-mediated decay supports PVS1 at very strong strength. Details ▾Hide ▴
Rule
TP53 VCEP PVS1: frameshift-induced premature termination codon upstream of p.Lys351 with predicted nonsense-mediated decay -> PVS1
Evidence considered
- Frameshift variant class
- Predicted protein consequence p.Ser90ProfsTer33 / p.S90Pfs*33
- Premature stop well upstream of p.Lys351
- TP53 VCEP null-variant PVS1 framework
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; an observed allele frequency of 0 is below the TP53 VCEP PM2 threshold of less than 0.00003. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: allele frequency <0.00003 in a large population dataset
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from population databases, so its allele frequency is below the TP53 BA1 threshold of 0.001 and BA1 is not met. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency >=0.001
Evidence considered
- Allele frequency 0 across reviewed population datasets
Sources
BS1 This variant is absent from population databases, so its allele frequency is below the TP53 BS1 threshold of 0.0003 and BS1 is not met. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency >=0.0003 and <0.001
Evidence considered
- Allele frequency 0 across reviewed population datasets
Sources
Not assessed · 6 · no assessment recorded
PS2 No de novo occurrence with confirmed maternity and paternity was identified, so PS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PS2 is point based and requires de novo evidence with phenotype weighting
Evidence considered
- No variant-specific de novo evidence identified
Still missing
- No confirmed de novo case was identified.
- No parental testing details were identified.
Sources
PS4 This variant has been reported in somatic cancers and in ClinVar, but no variant-specific TP53 proband data with Li-Fraumeni syndrome point totals were identified to show that the PS4 threshold was met. Details ▾Hide ▴
Rule
TP53 VCEP PS4 requires 1-1.5 points for Supporting, 2-3.5 for Moderate, 4-7.5 for Strong, and >=8 for Very Strong
Evidence considered
- COSMIC somatic count of 30
- ClinVar pathogenic/likely pathogenic submissions
- No TP53 PS4 point-based germline case evidence identified
Still missing
- No affected-proband point count under the TP53 PS4 framework was identified.
- No variant-specific germline case series sufficient for PS4 scoring was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires 3-4 meioses for Supporting, 5-6 for Moderate, and >=7 across >1 family for Strong
Evidence considered
- No family segregation evidence identified
Still missing
- No informative meioses were identified.
- No family-level co-segregation report was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction data or constitutional mosaicism evidence was identified, so the TP53-specific PP4 criteria based on low-level variant observations cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP4 requires blood observations with VAF 5-35%
Evidence considered
- TP53-specific PP4 requires low-VAF observations
Still missing
- No variant allele fraction data were identified.
- No multiple low-level blood observations were identified.
Sources
BS2 No evidence was identified showing this variant in unrelated females aged 60 years or older without cancer from a single source, so BS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is based on unaffected older female carriers from a single source
Evidence considered
- No qualifying unaffected-carrier evidence identified
Still missing
- No unaffected older female carrier series was identified.
Sources
BS4 No informative lack-of-segregation data were identified in affected family members, so BS4 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in family members affected with Li-Fraumeni syndrome-associated cancers
Evidence considered
- No family non-segregation evidence identified
Still missing
- No genotype-phenotype discordance data were identified in affected relatives.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change that results in the same amino acid substitution as an established TP53 pathogenic or likely pathogenic variant. This variant is a frameshift and does not meet that rule structure. Details ▾Hide ▴
Rule
TP53 VCEP PS1 is substitution based
Evidence considered
- Frameshift consequence rather than same-amino-acid substitution logic
Sources
PS3 N/AThe TP53 VCEP PS3 framework and supporting functional worksheet are designed for missense variants and small in-frame deletions. This variant is a frameshift, so PS3 is not applied from those resources. Details ▾Hide ▴
Rule
TP53 VCEP PS3 protein-function rules apply to missense variants and small in-frame deletions
Evidence considered
- TP53 functional rule scope is missense and small in-frame deletions
- Variant is a frameshift
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:11753428 ↗PMID:11900253 ↗PMID:16007150 ↗PMID:19336573 ↗PMID:21467160 ↗PMID:27759562 ↗
PM1 N/APM1 in the TP53 framework applies to missense variants at specified hotspot codons or recurrent somatic missense substitutions. This variant is a frameshift, and no hotspot-based missense rule applies. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to hotspot missense variants
Evidence considered
- Frameshift variant class
- No statistically significant hotspot row identified
Sources
PM3 VCEPPM3 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
PM4 VCEPPM4 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
PM5 N/APM5 in the TP53 framework is classic same-residue missense logic. This variant is a frameshift and is not eligible for PM5. Details ▾Hide ▴
Rule
TP53 VCEP PM5 applies only to missense variants at the same residue
Evidence considered
- PM5 candidate review found the variant class was not missense-like
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is designated not applicable in the TP53 VCEP framework; de novo evidence is handled through PS2. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
PP2 VCEPPP2 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
PP3 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the TP53 splice-evidence threshold of 0.2), and the TP53 PP3 framework is not designed to add separate computational evidence for this early frameshift in this context. Details ▾Hide ▴
Rule
TP53 VCEP PP3 uses missense/in-frame/synonymous/intronic computational rules and splice prediction threshold >=0.2
Evidence considered
- SpliceAI max delta score 0.07
- Frameshift variant class
Sources
PP5 VCEPPP5 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BS3 N/AThe TP53 VCEP BS3 framework and supporting functional worksheet are designed for missense variants and small in-frame deletions. This variant is a frameshift, so BS3 is not applied from those resources. Details ▾Hide ▴
Rule
TP53 VCEP BS3 protein-function rules apply to missense variants and small in-frame deletions
Evidence considered
- TP53 functional rule scope is missense and small in-frame deletions
- Variant is a frameshift
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:11753428 ↗PMID:11900253 ↗PMID:16007150 ↗PMID:19336573 ↗PMID:21467160 ↗PMID:27759562 ↗
BP1 VCEPBP1 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BP2 VCEPBP2 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BP3 VCEPBP3 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but the TP53 BP4 framework does not provide a benign computational code for this frameshift context. Details ▾Hide ▴
Rule
TP53 VCEP BP4 uses missense/in-frame/synonymous/intronic computational rules
Evidence considered
- SpliceAI max delta score 0.07
- Frameshift variant class
Sources
BP5 VCEPBP5 is designated not applicable in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BP6 VCEPBP6 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable per TP53 VCEP
Evidence considered
- TP53 VCEP applicability statement
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is a frameshift and BP7 does not apply. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or qualifying intronic variants
Evidence considered
- Frameshift variant class
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.267del
- Protein (HGVS p.)
- NP_000537.3:p.(Ser90ProfsTer33)
- GRCh38
- chr17:7676101 AG>A
- GRCh37
- chr17:7579419 AG>A
- ClinVar
- 156515
- COSMIC
- COSV52685476
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.
TP53NM_000546.6
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the TP53 splice-evidence threshold of 0.2), and the TP53 PP3 framework is not designed to add separate computational evidence for this early frameshift in this context. Details ▾Hide ▴
Rule
TP53 VCEP PP3 uses missense/in-frame/synonymous/intronic computational rules and splice prediction threshold >=0.2
Evidence considered
- SpliceAI max delta score 0.07
- Frameshift variant class
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.07), but the TP53 BP4 framework does not provide a benign computational code for this frameshift context. Details ▾Hide ▴
Rule
TP53 VCEP BP4 uses missense/in-frame/synonymous/intronic computational rules
Evidence considered
- SpliceAI max delta score 0.07
- Frameshift variant class
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is a frameshift and BP7 does not apply. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or qualifying intronic variants
Evidence considered
- Frameshift variant class
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 = 0.07).
9 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
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PMID 11753428 ↗A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.No paper-specific finding is recorded.
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PMID 11900253 ↗Rescuing the function of mutant p53.No paper-specific finding is recorded.
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PMID 16007150 ↗The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.No paper-specific finding is recorded.
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PMID 19336573 ↗High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.No paper-specific finding is recorded.
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PMID 21467160 ↗Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.No paper-specific finding is recorded.
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PMID 27759562 ↗TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions.No paper-specific finding is recorded.
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PMID 22233476 ↗Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations.Choong SS et al. · 2012No paper-specific finding is recorded.
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PMID 22733133 ↗The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression.Bernard H et al. · 2013No paper-specific finding is recorded.
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PMID 18414213 ↗ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.Richards CS et al. · 2008No paper-specific finding is recorded.
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 0.070
Open source ↗
ClinVar
2 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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/156515/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579419-AG-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676101-AG-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7676101-AG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.267d…
- OncoKB ↗www.oncokb.org/gene/TP53/S90Pfs*33
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121487773
- Cancer hotspots ↗www.cancerhotspots.org/
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 (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 156515)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
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; COSV52685476, n = 30 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.