About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.832_839dup, p.(Arg280SerfsTer68)
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 variant is a frameshift duplication in TP53 predicted to produce p.(Arg280SerfsTer68). Under the TP53 VCEP PVS1 flowchart, frameshift variants with a premature termination codon upstream of p.Lys351 are expected to undergo nonsense-mediated decay and meet PVS1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below 0.00004 within any non-founder ancestry group.
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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies 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.832_839dup (p.Arg280SerfsTer68) variant has not been observed in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity below the TP53 VCEP PM2 threshold.
The duplication causes a frameshift predicted to truncate TP53 at p.Arg280SerfsTer68, and because the premature stop is upstream of p.Lys351, the TP53 VCEP PVS1 flowchart supports PVS1.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a frameshift duplication in TP53 predicted to produce p.(Arg280SerfsTer68). Under the TP53 VCEP PVS1 flowchart, frameshift variants with a premature termination codon upstream of p.Lys351 are expected to undergo nonsense-mediated decay and meet PVS1. Details ▾Hide ▴
Rule
TP53 VCEP PVS1: frameshift-induced premature termination codon upstream of p.Lys351 = PVS1.
Evidence considered
- Protein consequence is p.(Arg280SerfsTer68).
- The affected residue is upstream of p.Lys351 in the TP53 PVS1 flowchart.
- TP53 loss of function is an established disease mechanism in the VCEP framework.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below 0.00004 within any non-founder ancestry group. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: allele frequency <0.00003 overall and <0.00004 in any non-founder ancestry group.
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 and does not reach the TP53 VCEP BA1 stand-alone benign threshold of at least 0.001. Details ▾Hide ▴
Evidence considered
- No population observations were identified.
Sources
BS1 This variant is absent from population databases and does not reach the TP53 VCEP BS1 benign threshold of at least 0.0003 in a qualifying ancestry group. Details ▾Hide ▴
Evidence considered
- No population observations were identified.
Sources
Not assessed · 6 · no assessment recorded
PS2 No confirmed de novo observations or point-based PS2 evidence were identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo evidence was provided.
Still missing
- No parental testing or de novo case data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 No proband-based Li-Fraumeni syndrome point data were identified to determine whether the TP53 VCEP PS4 thresholds are met. Population rarity supports eligibility to consider PS4, but case-level observations were not available. Details ▾Hide ▴
Evidence considered
- Variant is population-rare.
- No PS4 point-based case observations were identified.
Still missing
- No qualifying proband cancer history or point total was identified.
Sources
PP1 No segregation data were identified to assess cosegregation with Li-Fraumeni syndrome-associated cancers. Details ▾Hide ▴
Evidence considered
- No segregation evidence was provided.
Still missing
- No family segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No phenotype-specific TP53 VCEP PP4 evidence was identified, including no low-variant-allele-fraction observation data needed for this rule. Details ▾Hide ▴
Evidence considered
- No PP4-qualifying phenotype data were provided.
Still missing
- No phenotype or blood variant allele fraction data were identified.
Sources
BS2 No data were identified showing this variant in unrelated females aged at least 60 years without cancer from a single source, so BS2 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No BS2 carrier evidence was identified.
Still missing
- No unaffected older female carrier data were identified.
Sources
BS4 No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No BS4 family evidence was identified.
Still missing
- No non-segregation data were identified.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is a same-amino-acid-change rule for variants that create an established pathogenic or likely pathogenic protein substitution. This variant is a frameshift duplication, so PS1 does not apply. Details ▾Hide ▴
PS3 N/AThe TP53 VCEP PS3 framework applies to missense variants and small in-frame deletions using eligible functional assays. This frameshift duplication is outside that assay-based framework, and no variant-specific TP53 VCEP functional worksheet entry was identified for this variant. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
- TP53 functional worksheet guidance is for missense variants and small deletions.
Sources
PM1 N/AThe TP53 VCEP PM1 rule is defined for missense hotspot variants. This variant is a frameshift duplication, so PM1 does not apply. Details ▾Hide ▴
PM3 VCEPPM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PM4 VCEPPM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PM5 N/AThe TP53 VCEP PM5 rule uses classic same-residue missense logic. This variant is not missense-like, and the PM5 candidate review marked the rule as not applicable. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found the variant is not eligible for classic same-residue missense PM5.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PP3 N/AThe TP53 VCEP PP3 framework is defined for missense variants, single amino acid in-frame deletions, and non-canonical splice-relevant exonic or intronic variants. This variant is a frameshift duplication, so PP3 is not applied. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
- SpliceAI max delta score = 0.00.
Sources
PP5 VCEPPP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BS3 N/AThe TP53 VCEP BS3 framework applies to missense variants and small in-frame deletions using eligible functional assays. This frameshift duplication is outside that framework, and no evidence was identified showing retained TP53 function for this variant. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
Sources
BP1 VCEPBP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP4 N/AThe TP53 VCEP BP4 framework is defined for missense variants, single amino acid in-frame deletions, and selected silent or intronic variants. This variant is a frameshift duplication, so BP4 is not applied, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
- SpliceAI max delta score = 0.00.
Sources
BP5 VCEPBP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP6 VCEPBP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is defined for synonymous and selected intronic variants. This variant is a frameshift duplication, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
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.832_839dup
- Protein (HGVS p.)
- NP_000537.3:p.(Arg280SerfsTer68)
- GRCh38
- chr17:7673780 T>TCTCCCAGG
- GRCh37
- chr17:7577098 T>TCTCCCAGG
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/AThe TP53 VCEP PP3 framework is defined for missense variants, single amino acid in-frame deletions, and non-canonical splice-relevant exonic or intronic variants. This variant is a frameshift duplication, so PP3 is not applied. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
- SpliceAI max delta score = 0.00.
Sources
BP4 N/AThe TP53 VCEP BP4 framework is defined for missense variants, single amino acid in-frame deletions, and selected silent or intronic variants. This variant is a frameshift duplication, so BP4 is not applied, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
- SpliceAI max delta score = 0.00.
Sources
BP7 N/ABP7 is defined for synonymous and selected intronic variants. This variant is a frameshift duplication, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift.
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 = 0.00).
6 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.
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 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000546.6%3Ac.832_839dup
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577098-T-TCTCCCAGG?datase…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7673780-T-TCTCCCAGG?dat…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7673780-T-TCTCCCAGG
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.832_…
- OncoKB ↗www.oncokb.org/gene/TP53/R280Sfs*68
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.832_839dup
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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 lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.