About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.580del, p.(Ile195SerfsTer52)
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
Frameshift deletion c.580del produces a premature termination codon at p.Ile195SerfsTer52 (PTC at codon 246), upstream of p.Lys351. The PTC is located in exon 6, not in exon 11 or the 3'-most 50 nucleotides of exon 10, and is therefore predicted to undergo nonsense-mediated decay. Per the TP53 VCEP PVS1 flowchart (v2.4.0), PVS1 at very strong weight is applied to frameshift-induced PTCs upstream of p.Lys351 that are predicted to undergo NMD.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the TP53 VCEP PM2 specifications, variants with an allele frequency below 0.00003 (0.003%) qualify for PM2 at supporting level. Complete absence from population databases satisfies this threshold.
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
NM_000546.5:c.580delC (p.Ile195SerfsTer52) is a frameshift deletion in exon 6 of TP53, producing a premature termination codon at position 246, upstream of p.Lys351, and is predicted to undergo nonsense-mediated decay. Under the TP53 VCEP PVS1 decision tree (v2.4.0), PVS1 is applied at very strong weight (8 points).
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under the TP53 VCEP PM2 specifications, variants with an allele frequency below 0.00003 qualify for PM2 at supporting level (1 point).
The variant is absent from ClinVar and has not been reported in COSMIC. No variant-specific functional data are available from the TP53 VCEP functional worksheet (which covers missense and in-frame deletions only). No proband phenotype, de novo, segregation, or VAF data are available in the case materials to assess PS2, PS4, PP1, PP4, BS2, or BS4.
Total weighted points: PVS1 (8) + PM2_Supporting (1) = 9 points. Per the TP53 VCEP Tavtigian Bayesian point-based classification framework (v2.4.0), 6-9 points corresponds to Likely Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongFrameshift deletion c.580del produces a premature termination codon at p.Ile195SerfsTer52 (PTC at codon 246), upstream of p.Lys351. The PTC is located in exon 6, not in exon 11 or the 3'-most 50 nucleotides of exon 10, and is therefore predicted to undergo nonsense-mediated decay. Per the TP53 VCEP PVS1 flowchart (v2.4.0), PVS1 at very strong weight is applied to frameshift-induced PTCs upstream of p.Lys351 that are predicted to undergo NMD. Details ▾Hide ▴
Evidence considered
- Frameshift deletion c.580del (NM_000546.5) results in PTC at codon 246 (p.Ile195SerfsTer52)
- PTC is upstream of p.Lys351
- satisfying the VCEP PVS1 decision tree criterion for full PVS1 weight
- PTC in exon 6 is not in exon 11 or the 3'-most 50 nt of exon 10
- NMD is predicted
- Loss of function is an established disease mechanism for TP53 (Li-Fraumeni syndrome
- autosomal dominant)
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the TP53 VCEP PM2 specifications, variants with an allele frequency below 0.00003 (0.003%) qualify for PM2 at supporting level. Complete absence from population databases satisfies this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
Not met · 2 · evaluated, threshold not reached
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. VCEP BA1 requires a filtering allele frequency ≥0.001 (0.1%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- does not meet BA1 FAF ≥0.001 threshold
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. VCEP BS1 requires a filtering allele frequency ≥0.0003 (0.03%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- does not meet BS1 FAF ≥0.0003 threshold
Sources
Not assessed · 6 · no assessment recorded
PS2 No de novo proband data or LFS cancer type scoring information available in the case materials. PS2 requires proband cancer data scored per the Table of LFS Cancers and Points for PS2 and PP1 Code Application. Details ▾Hide ▴
Still missing
- No proband phenotype or de novo confirmation data available
PS4 No proband data with Li-Fraumeni syndrome cancer type scoring available. PS4 requires tallying proband points per the VCEP PS4 Points Table (strongly associated cancers: 4 points; moderately associated: 2 points) and Chompret criteria assessment. Details ▾Hide ▴
Still missing
- No proband phenotype or LFS cancer scoring data available
PP1 No cosegregation data available. VCEP PP1 requires observation of cosegregation in 3-4 meioses (supporting), 5-6 meioses (moderate), or ≥7 meioses across >1 family (strong), with affected individuals having LFS-associated cancers. Details ▾Hide ▴
Still missing
- No family cosegregation data available
PP4 No variant allele fraction (VAF) data available. VCEP PP4 requires observation of the variant with VAF 5-35% (supporting) or at least 2 independent observations with VAF 5-25% (moderate) to support constitutional mosaicism or low-level somatic findings. Details ▾Hide ▴
Still missing
- No VAF or patient phenotype data available
BS2 No data on cancer-free females ≥60 years of age available. VCEP BS2 requires 2-3 (supporting), 4-7 (moderate), or ≥8 (strong) unrelated females who have reached at least 60 years without cancer, all from a single source. Details ▾Hide ▴
Still missing
- No data on cancer-free elderly females available
BS4 No segregation data available. VCEP BS4 requires lack of segregation in affected family members diagnosed with LFS-associated cancers. Details ▾Hide ▴
Still missing
- No family segregation data available
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change producing the same amino acid change as a previously established pathogenic variant. This variant is a frameshift deletion, not an amino acid substitution, and PS1 is not applicable to this variant class under the TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- PS1 is defined for amino acid substitutions only
Sources
PS3 N/AThe TP53 VCEP PS3/BS3 functional assay pathway applies to missense variants and small in-frame deletions, assessed via the Functional-worksheet.xlsx (Kato, Funk, Giacomelli, Kotler, Kawaguchi assays). This variant is a frameshift deletion producing a truncated protein, not a missense or in-frame deletion. The VCEP functional rules do not cover frameshift truncations for PS3/BS3 assessment. The Functional-worksheet.xlsx contains entries for amino acid substitutions at position 195 but no entry for the frameshift p.Ile195SerfsTer52. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift truncation
- not covered by VCEP functional assay pathway
- Functional-worksheet.xlsx contains I195 amino acid substitutions only
- no frameshift entry
Sources
PM1 N/AVCEP PM1 applies exclusively to missense variants at codons 175, 245, 248, 249, 273, 282 or germline missense variants in cancerhotspots.org with somatic occurrence thresholds. This variant is a frameshift deletion, not a missense variant, and PM1 is not applicable to this variant class under the TP53 VCEP specifications. Details ▾Hide ▴
PM4 VCEPPM4 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Details ▾Hide ▴
PM5 N/AVCEP PM5 applies exclusively to missense variants at an amino acid residue where a different pathogenic or likely pathogenic missense variant has been previously identified. This variant is a frameshift deletion, not a missense substitution, and PM5 is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- PM5 rules specify missense variants only
- pm5_candidates.json confirms not applicable for non-missense variant class
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. The VCEP uses a combined PS2/PM6 rule under the PS2 criterion. Details ▾Hide ▴
PP2 VCEPPP2 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Details ▾Hide ▴
PP3 N/AVCEP PP3 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using aGVGD/BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or the PP3-BP4-codes.xlsx or the TP53 single amino acid deletion BayesDel spreadsheet. The variant is not listed in any VCEP in silico code assignment resource. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- PP3 rules apply to missense
- synonymous
- intronic
- and in-frame deletions only
- SpliceAI max delta = 0.00 (no predicted splicing impact)
- but PP3 does not apply to frameshift variants regardless
Sources
PP5 VCEPPP5 is explicitly marked as not applicable for this VCEP in the TP53 VCEP ACMG/AMP Specifications v2.4.0, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS3 N/AThe TP53 VCEP BS3/PS3 functional assay pathway applies to missense variants and small in-frame deletions, assessed via the Functional-worksheet.xlsx. This variant is a frameshift deletion producing a truncated protein, not a missense or in-frame deletion, and is not covered by the VCEP functional rules. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift truncation
- not covered by VCEP functional assay pathway
Sources
BP1 VCEPBP1 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Truncating variants account for a significant portion of disease-causing variants in TP53. Details ▾Hide ▴
BP2 VCEPBP2 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Details ▾Hide ▴
BP3 VCEPBP3 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Details ▾Hide ▴
BP4 N/AVCEP BP4 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or associated spreadsheets. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- BP4 rules apply to missense
- synonymous
- intronic
- and in-frame deletions only
Sources
BP5 VCEPBP5 is explicitly marked as not applicable in the TP53 VCEP ACMG/AMP Specifications v2.4.0. Details ▾Hide ▴
BP6 VCEPBP6 is explicitly marked as not applicable for this VCEP in the TP53 VCEP ACMG/AMP Specifications v2.4.0, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/AVCEP BP7 applies to synonymous (silent) or intronic variants. This variant is a frameshift deletion, not a synonymous or intronic variant, and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- BP7 rules specify synonymous or intronic variants only
Sources
PS5 N/APS5 is not included in the TP53 VCEP ACMG/AMP Specifications v2.4.0 criteria set. Not applicable under the governing VCEP framework. Details ▾Hide ▴
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.580del
- Protein (HGVS p.)
- NP_000537.3:p.(Ile195SerfsTer52)
- GRCh38
- chr17:7674950 AG>A
- GRCh37
- chr17:7578268 AG>A
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…
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/AVCEP PP3 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using aGVGD/BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or the PP3-BP4-codes.xlsx or the TP53 single amino acid deletion BayesDel spreadsheet. The variant is not listed in any VCEP in silico code assignment resource. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- PP3 rules apply to missense
- synonymous
- intronic
- and in-frame deletions only
- SpliceAI max delta = 0.00 (no predicted splicing impact)
- but PP3 does not apply to frameshift variants regardless
Sources
BP4 N/AVCEP BP4 applies to missense, synonymous, intronic, and single amino acid in-frame deletion variants using BayesDel scores and SpliceAI predictions. This variant is a frameshift deletion, which is not covered by the VCEP PP3/BP4 flowchart or associated spreadsheets. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- BP4 rules apply to missense
- synonymous
- intronic
- and in-frame deletions only
Sources
BP7 N/AVCEP BP7 applies to synonymous (silent) or intronic variants. This variant is a frameshift deletion, not a synonymous or intronic variant, and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is a frameshift
- BP7 rules specify synonymous or intronic variants only
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
5 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.Reports pH-dependent destabilization of the p53-R337H mutant tetramerization domain in pediatric adrenocortical carcinoma. NM_000546.5:c.580delC was not identified in this paper.Does not name this variant
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PMID 11900253 ↗Rescuing the function of mutant p53.General review discussing strategies to restore function to mutant p53 through small molecules and peptides. NM_000546.5:c.580delC was not identified in this paper.Does not name this variant
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PMID 16007150 ↗The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.Comprehensive missense mutation library analysis of p53 oligomerization domain structure-function relationships using 184 mutants. NM_000546.5:c.580delC was not identified in this paper.Does not name this variant
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PMID 19336573 ↗High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.Reports high incidence of protein-truncating TP53 mutations (nonsense, frameshift, splice) in BRCA1-related breast cancers. Specific TP53 mutations identified include c.110delC, c.145delG, c.167insA, c.258delG, c.239insT, and c.184insA. NM_000546.5:c.580delC was not identified in this paper.Does not name this variant
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PMID 21467160 ↗Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.Reports prognostic significance of truncating TP53 mutations (nonsense, frameshift, splice-site) in head and neck squamous cell carcinoma. Truncating mutations were associated with worse overall and progression-free survival. NM_000546.5:c.580delC was not identified in this paper.Does not name this variant
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_000546.5%3Ac.580delC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578268-AG-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674950-AG-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7674950-AG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.580d…
- OncoKB ↗www.oncokb.org/gene/TP53/I195Sfs*52
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.580del
- 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.