About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.612_623del, p.(Glu204_Asp207del)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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. 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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is below the VCEP PM2_Supporting threshold of 0.00003 (0.003%).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
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 does not lie in a statistically significant hotspot.
Context only
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: 1 met · 4 not met · 8 not assessed · 15 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.612_623del (p.Glu204_Asp207del) is an in-frame deletion of 12 nucleotides in exon 6 of TP53, removing four amino acids (204-207) within the DNA-binding core domain (residues 102-292).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles across all population databases), meeting PM2_Supporting under the TP53 VCEP (AF < 0.00003).
The variant is absent from ClinVar and has not been previously classified by any diagnostic laboratory or expert panel.
The variant is not a null variant (nonsense, frameshift, or canonical splice) and is not addressed by the TP53 VCEP PVS1 decision tree, which covers only truncating and exon-level deletion variants. PVS1 is not applicable.
No variant-specific functional data are available. The VCEP Functional-worksheet catalogs single amino acid substitutions and deletions but does not include the 4-amino-acid deletion p.Glu204_Asp207del. Two reviewed publications (PMID:11900253, PMID:8023157) discuss p53 structure and function at the gene level but do not mention this specific variant.
Several criteria (PS2, PS4, PP1, PP4, BS2, BS4) could not be assessed due to absence of proband phenotype, family, or segregation data. Multiple VCEP criteria (PM4, PM6, PP2, PP5, BP1, BP2, BP3, BP5, BP6) are explicitly marked as Not Applicable under the TP53 VCEP v2.4 framework.
The only applicable and met criterion is PM2_Supporting (absent from population databases). All other assessable criteria are either not applicable, not met, or not assessed due to insufficient data.
No criteria match.
Met · 1
PM2 SupportingNM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is below the VCEP PM2_Supporting threshold of 0.00003 (0.003%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada v1.0 (0 alleles). AF = 0
- well below VCEP PM2_Supporting threshold of <0.00003.
Sources
Not met · 4 · evaluated, threshold not reached
PS1 No variant with the same amino acid change (p.Glu204_Asp207del) has been previously classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. This variant is absent from ClinVar and no prior VCEP-classified comparator exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-amino-acid-change comparator with prior VCEP P/LP classification.
Sources
BA1 NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is far below the VCEP BA1 stand-alone threshold of ≥0.001 (0.1%) in any continental subpopulation. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets. AF = 0
- well below BA1 threshold of ≥0.001.
Sources
BS1 NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is below the VCEP BS1 strong threshold of ≥0.0003 (0.03%) in any continental subpopulation with ≥2,000 alleles and ≥2 variant alleles. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets. AF = 0
- below BS1 threshold of ≥0.0003.
Sources
PS5 No reputable source has reported NM_000546.5:c.612_623del as pathogenic. The variant is absent from ClinVar and no published classification from a diagnostic laboratory or expert panel was identified. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no prior pathogenic classification from any source.
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observation data available. VCEP PS2 requires proband-level cancer diagnosis and confirmed parentage to assign points based on the LFS cancer scoring table. No proband or family data were provided for this case. Details ▾Hide ▴
Still missing
- No proband phenotype data
- no parental testing results
- no de novo confirmation available.
PS3 The TP53 VCEP Functional-worksheet (Supplementary Table S3) catalogs PS3/BS3 assignments for single amino acid substitutions and single amino acid deletions but does not contain an entry for the 4-amino-acid deletion p.Glu204_Asp207del. No variant-specific functional assay data were identified in the two publications reviewed (PMID:11900253, PMID:8023157), neither of which mentions this variant. OncoKB annotates this variant as Likely Oncogenic/Likely Loss-of-function, but this represents somatic curated inference rather than direct germline functional evidence qualifying for PS3 under VCEP rules. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet lacks entry for p.E204_D207del
- only single-residue substitutions at E204 and D207 are cataloged. OncoKB Likely Oncogenic annotation is somatic context
- not direct germline functional assay data.
Still missing
- No variant-specific functional assay data (Kato
- Funk
- Giacomelli
- Kotler
- or Kawaguchi) for the 4-aa deletion p.Glu204_Asp207del.
Sources
vcep_functional_worksheetoncokb ↗
PS4 VCEP PS4 uses a point-based system requiring proband-level cancer diagnoses matched to the LFS cancer scoring table. No proband phenotype data were provided. The variant is absent from ClinVar and COSMIC, providing no population-level case data. Details ▾Hide ▴
Still missing
- No proband cancer diagnoses available for VCEP PS4 point calculation.
PP1 No cosegregation data available. VCEP PP1 requires observation in 3-4 meioses for supporting, 5-6 for moderate, or ≥7 for strong across families. No family or segregation data were provided. Details ▾Hide ▴
Still missing
- No family structure
- affected status
- or segregation data available.
PP4 VCEP PP4 requires observation of the variant at low variant allele fraction (VAF 5-35%) in blood, suggestive of somatic mosaicism or clonal hematopoiesis. No VAF or phenotype data were provided for this case. Details ▾Hide ▴
Still missing
- No VAF or phenotype data available for PP4 assessment.
BS2 VCEP BS2 requires ≥2 unrelated females aged ≥60 years without cancer (supporting) from a single source, excluding sarcoma diagnoses at ≥61 years. No such data were provided for this variant. Details ▾Hide ▴
Still missing
- No healthy elderly female observational data available.
BS3 The TP53 VCEP Functional-worksheet does not contain an entry for p.Glu204_Asp207del. Single amino acid substitutions at E204 and D207 show mixed functional outcomes (BS3 for most substitutions; PS3_Moderate for E204G and D207G), but these do not represent functional data for the 4-amino-acid deletion. No variant-specific functional data were identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet catalogs single-residue substitutions only. No BS3 assignment exists for p.E204_D207del.
Still missing
- No functional assay data for the 4-aa deletion to support BS3 application.
Sources
vcep_functional_worksheet
BS4 VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. No family or segregation data were provided. Details ▾Hide ▴
Still missing
- No family segregation data available.
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000546.5:c.612_623del is an in-frame deletion removing 4 amino acids (p.Glu204_Asp207del) without introducing a premature termination codon. The TP53 VCEP PVS1 flowchart (v2.4) covers nonsense, frameshift, canonical splice site, and exon-level deletion variants only. In-frame deletions are not addressed by the PVS1 decision tree and do not qualify as null variants under the VCEP framework. Details ▾Hide ▴
Evidence considered
- In-frame deletion of 12 bp in exon 6
- no PTC introduced
- VCEP PVS1 flowchart does not cover in-frame deletions.
Sources
vcep_pvs1_flowchartpvs1_variant_assessment
PM1 N/AThe TP53 VCEP PM1 rule (v2.4) is restricted to missense variants at six specified hotspot codons (175, 245, 248, 249, 273, 282) for moderate strength, or missense variants with cancerhotspots.org somatic counts for supporting strength. NM_000546.5:c.612_623del is an in-frame deletion, not a missense variant. Under VCEP specifications, PM1 is not applicable to non-missense variant types. Details ▾Hide ▴
Evidence considered
- VCEP PM1 restricted to missense variants at codons 175/245/248/249/273/282 or cancerhotspots.org missense counts. This is an in-frame deletion at codons 204-207
- none of which are VCEP-designated PM1 hotspots.
Sources
PM4 VCEPThe TP53 VCEP (v2.4) explicitly marks PM4 as Not Applicable. This criterion is not used under the gene-specific framework. Details ▾Hide ▴
PM5 N/AThe TP53 VCEP PM5 rule applies to missense variants at an amino acid residue where a different missense change has been classified as P/LP. NM_000546.5:c.612_623del is a 4-amino-acid in-frame deletion, not a missense substitution. The variant class does not fit the PM5 framework. Details ▾Hide ▴
Evidence considered
- VCEP PM5 restricted to missense variants
- this is an in-frame deletion. pm5_candidates.json confirms not_applicable.
Sources
cspec ↗pm5_candidates
PM6 VCEPThe TP53 VCEP (v2.4) explicitly marks PM6 as Not Applicable; de novo evidence is assessed under PS2 using the combined PS2/PM6 point system. Details ▾Hide ▴
Evidence considered
- VCEP PM6 applicability: Not Applicable. De novo evidence assessed under PS2.
Sources
PP2 VCEPThe TP53 VCEP (v2.4) explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
PP3 N/AThe TP53 VCEP in silico framework (PP3-BP4 flowchart and PP3-BP4-codes.xlsx) covers missense, synonymous, and intronic variants. Single amino acid in-frame deletions are addressed by the TP53-single-amino-acid-deletions-BayesDel-scores spreadsheet. This variant is a 4-amino-acid in-frame deletion, a variant type not covered by any VCEP in silico prediction framework. SpliceAI predicts no splicing impact (max delta = 0.00). No BayesDel or REVEL score is available for this multi-residue deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact). VCEP PP3 framework does not cover multi-residue in-frame deletions. PP3-BP4-codes.xlsx does not contain c.612_623del. Single-aa BayesDel spreadsheet contains E204del and D207del individually but not the combined 4-aa deletion.
Sources
PP5 VCEPThe TP53 VCEP (v2.4) explicitly marks PP5 as Not Applicable. Per the user's global PP5 rule, ClinVar 3-star expert panel classification could override this, but the variant is absent from ClinVar entirely, so no override applies. Details ▾Hide ▴
BP1 VCEPThe TP53 VCEP (v2.4) explicitly marks BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in TP53. Details ▾Hide ▴
BP2 VCEPThe TP53 VCEP (v2.4) explicitly marks BP2 as Not Applicable. Details ▾Hide ▴
BP3 VCEPThe TP53 VCEP (v2.4) explicitly marks BP3 as Not Applicable. Details ▾Hide ▴
BP4 N/AThe TP53 VCEP in silico framework for BP4 covers missense, synonymous, intronic, and single amino acid in-frame deletion variants. This variant is a 4-amino-acid in-frame deletion, a variant type not addressed by any VCEP in silico prediction framework. No BayesDel score is available for this multi-residue deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact). VCEP BP4 framework does not cover multi-residue in-frame deletions. Single-aa BayesDel spreadsheet does not contain the combined 4-aa deletion.
Sources
BP5 VCEPThe TP53 VCEP (v2.4) explicitly marks BP5 as Not Applicable. Details ▾Hide ▴
BP6 VCEPThe TP53 VCEP (v2.4) explicitly marks BP6 as Not Applicable. Per the user's global BP6 rule, ClinVar 3-star expert panel benign classification could override this, but the variant is absent from ClinVar, so no override applies. Details ▾Hide ▴
BP7 N/AVCEP BP7 applies to synonymous (silent) or intronic variants with no predicted splicing impact. NM_000546.5:c.612_623del is an in-frame deletion, not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- BP7 restricted to synonymous/intronic variants
- this is an in-frame deletion.
Sources
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.612_623del
- Protein (HGVS p.)
- NP_000537.3:p.(Glu204_Asp207del)
- GRCh38
- chr17:7674907 GTCATCCAAATAC>G
- GRCh37
- chr17:7578225 GTCATCCAAATAC>G
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/AThe TP53 VCEP in silico framework (PP3-BP4 flowchart and PP3-BP4-codes.xlsx) covers missense, synonymous, and intronic variants. Single amino acid in-frame deletions are addressed by the TP53-single-amino-acid-deletions-BayesDel-scores spreadsheet. This variant is a 4-amino-acid in-frame deletion, a variant type not covered by any VCEP in silico prediction framework. SpliceAI predicts no splicing impact (max delta = 0.00). No BayesDel or REVEL score is available for this multi-residue deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact). VCEP PP3 framework does not cover multi-residue in-frame deletions. PP3-BP4-codes.xlsx does not contain c.612_623del. Single-aa BayesDel spreadsheet contains E204del and D207del individually but not the combined 4-aa deletion.
Sources
BP4 N/AThe TP53 VCEP in silico framework for BP4 covers missense, synonymous, intronic, and single amino acid in-frame deletion variants. This variant is a 4-amino-acid in-frame deletion, a variant type not addressed by any VCEP in silico prediction framework. No BayesDel score is available for this multi-residue deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact). VCEP BP4 framework does not cover multi-residue in-frame deletions. Single-aa BayesDel spreadsheet does not contain the combined 4-aa deletion.
Sources
BP7 N/AVCEP BP7 applies to synonymous (silent) or intronic variants with no predicted splicing impact. NM_000546.5:c.612_623del is an in-frame deletion, not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- BP7 restricted to synonymous/intronic variants
- this is an in-frame deletion.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
2 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
-
PMID 11900253 ↗Rescuing the function of mutant p53.Review article discussing p53 structure, mutational hotspots, thermodynamic stability of core domain mutations, and strategies for pharmacological rescue of mutant p53. Describes five mutational classes based on folding and DNA-binding competence. NM_000546.5:c.612_623del (p.Glu204_Asp207del) was not identified in this paper.Does not name this variant
-
PMID 8023157 ↗Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.Reports the crystal structure of the human p53 core domain (residues 94-312) bound to a consensus DNA binding site at 2.2 angstrom resolution. Identifies the DNA-binding surface comprising loop-sheet-helix motif and two large loops stabilized by zinc coordination. Confirms the core domain (residues 102-292) as the minimal sequence-specific DNA binding region. NM_000546.5:c.612_623del (p.Glu204_Asp207del) 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.612_623del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578225-GTCATCCAAATAC-G?da…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674907-GTCATCCAAATAC-G…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7674907-GTCATCCAAATAC-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.612_…
- OncoKB ↗www.oncokb.org/gene/TP53/E204_D207del
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.612_623del
- 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 does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.