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TP53c.599_600delLikely pathogenic
Print report
Variant interpretation report

TP53 c.599_600del, p.(Asn200IlefsTer8)

NM_000546.6:c.599_600del NP_000537.3:p.(Asn200IlefsTer8) 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

No gene-level summary was recorded for this case.

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

This 2-base-pair deletion in exon 6 produces a frameshift (p.Asn200IlefsTer8) with a premature termination codon at approximately codon 207, upstream of p.Lys351 and predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength per the TP53 VCEP decision tree.

PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency below 0.003%).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 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.

SpliceAI score
0.048 maximum delta

Recorded SpliceAI maximum delta score: 0.048. 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

29 criteria with recorded statuses: 2 met · 11 not met · 0 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This two-base-pair deletion in TP53 exon 6 produces a frameshift (p.Asn200IlefsTer8) with a premature termination codon at approximately codon 207, upstream of p.Lys351 and predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the TP53 VCEP decision tree.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting at an allele frequency below 0.003%.

Absence from population databases is consistent with a pathogenic role and does not satisfy any benign frequency criterion (BA1, BS1).

No variant-specific functional, segregation, de novo, or clinical observations were identified, and none of the reviewed publications mentions NM_000546.6:c.599_600del; therefore no additional pathogenic or benign criteria are met.

Met · 2

PVS1 Very strongThis 2-base-pair deletion in exon 6 produces a frameshift (p.Asn200IlefsTer8) with a premature termination codon at approximately codon 207, upstream of p.Lys351 and predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength per the TP53 VCEP decision tree. Details ▾Hide ▴
Evidence considered
  • Frameshift variant (c.599_600del) with PTC at p.Asn200IlefsTer8 (~codon 207).
  • PTC located in exon 6
  • upstream of p.Lys351
  • and not in exon 11 or the 3'-most 50 nt of exon 10
  • NMD is predicted.
  • Germline loss of function is an established TP53/Li-Fraumeni syndrome disease mechanism per the TP53 VCEP.
Sources
cspec ↗vcep_pvs1_flowchartpvs1_variant_assessmentpvs1_gene_context
PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2_Supporting (allele frequency below 0.003%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exome).
  • Absent from gnomAD v4.1 (exome).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Not met · 11 · evaluated, threshold not reached

PS2 No de novo observation of this variant was identified; no proband or confirmed parental testing data are available to tally de novo points. Details ▾Hide ▴
Evidence considered
  • No de novo report for NM_000546.6:c.599_600del was identified in ClinVar or the literature packet.
Still missing
  • No proband/parental genotype data available to assess de novo occurrence.
Sources
cspec ↗
PS3 No functional data exist for this frameshift variant. It is not present in the TP53 VCEP functional worksheet (which covers amino acid substitutions and single-amino-acid in-frame deletions), and none of the reviewed publications tested NM_000546.6:c.599_600del. Details ▾Hide ▴
Evidence considered
  • Frameshift p.Asn200IlefsTer8 is not listed in the TP53 VCEP Functional-worksheet (Supplementary Table S3).
  • The five triaged functional publications (11753428
  • 11900253
  • 16007150
  • 19336573
  • 21467160) do not mention this variant.
  • OncoKB labels the variant Likely Oncogenic / likely loss-of-function in a somatic curation context
  • this is not germline functional assay evidence for PS3.
Still missing
  • No variant-specific functional assay data available.
Sources
cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesoncokb ↗
PS4 No affected-proband observations were identified; the variant is absent from ClinVar and COSMIC, and no case-control prevalence data are available to tally PS4 points. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar (no clinical submissions).
  • Variant has not been reported in COSMIC somatic cancers.
  • No Li-Fraumeni syndrome proband data provided.
Still missing
  • No affected individual observations or case-control data.
Sources
clinvar ↗cspec ↗
PM1 This frameshift at codon 200 does not fall within a TP53 VCEP-defined hotspot codon (175, 245, 248, 249, 273, 282), which applies only to missense variants, and it is not a cancerhotspots.org missense change with qualifying somatic occurrences. Details ▾Hide ▴
Evidence considered
  • Variant position (codon 200) is not a TP53 VCEP hotspot codon.
  • Variant is a frameshift
  • not a missense
  • so the cancerhotspots.org PM1 rules do not apply.
  • No statistically significant hotspot is reported for this variant.
Sources
cspec ↗
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family/segregation observations were identified in ClinVar or the literature packet.
Still missing
  • No cosegregation data available.
Sources
cspec ↗
PP4 No proband phenotype or variant allele fraction (VAF) data are available to satisfy the TP53 VCEP PP4 rule, which requires somatic VAF observations (5-35%). Details ▾Hide ▴
Evidence considered
  • No patient VAF or phenotype data provided.
Still missing
  • No proband phenotype/VAF data available.
Sources
cspec ↗
BA1 The variant is absent from gnomAD and does not reach the stand-alone benign allele frequency threshold (>=0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗
BS1 The variant is absent from gnomAD and does not meet the strong benign allele frequency threshold (>=0.0003). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗
BS2 No unaffected adult (cancer-free female >=60 years) observations are available for this variant. Details ▾Hide ▴
Evidence considered
  • No BS2-qualifying unaffected individual data available.
Still missing
  • No unaffected adult observations available.
Sources
cspec ↗
BS3 No functional data demonstrate a benign (normal function) effect for this frameshift variant; it is not present in the TP53 VCEP functional worksheet and no reviewed publication tested it. Details ▾Hide ▴
Evidence considered
  • Frameshift p.Asn200IlefsTer8 is not listed in the TP53 VCEP Functional-worksheet.
  • No variant-specific benign functional evidence identified.
Still missing
  • No variant-specific functional data available.
Sources
cspec ↗vcep_functional_worksheet
BS4 No segregation data are available to assess lack of segregation among affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation observations identified.
Still missing
  • No segregation data available.
Sources
cspec ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 (same amino acid change as a previously established pathogenic variant) applies to missense/substitution comparisons; this is a frameshift deletion with no same-change comparator, and the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Frameshift variant does not map to a single amino acid change for PS1 comparison.
  • Variant is absent from ClinVar
  • so no previously classified comparator exists.
Sources
cspec ↗clinvar ↗
PM3 VCEPTP53/Li-Fraumeni syndrome is autosomal dominant; PM3 (recessive trans observation) does not apply. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP marks PM3 as not applicable for Li-Fraumeni syndrome.
Sources
cspec ↗
PM4 VCEPThe TP53 VCEP marks PM4 as Not Applicable; in-frame length changes are addressed by the PVS1 flowchart and this variant is a frameshift already captured by PVS1. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies PM4 as Not Applicable.
Sources
cspec ↗
PM5 N/APM5 applies to missense changes at a residue with an established pathogenic/likely pathogenic missense comparator; this is a frameshift, not a missense, and no comparator was identified. Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not missense-like
  • PM5 same-residue missense comparison does not apply.
  • Variant is absent from ClinVar
  • no comparator pathogenic variant exists.
Sources
cspec ↗pm5_candidatesclinvar ↗
PM6 VCEPThe TP53 VCEP uses points-based PS2 for de novo evidence and marks PM6 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies PM6 as Not Applicable (see PS2 combined rule).
Sources
cspec ↗
PP2 VCEPThe TP53 VCEP marks PP2 as Not Applicable; additionally this is a frameshift, not a missense variant. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies PP2 as Not Applicable.
Sources
cspec ↗
PP3 N/AThe TP53 VCEP PP3 in-silico rules apply only to missense variants, single-amino-acid in-frame deletions, and splice variants; this is a frameshift, and SpliceAI predicts no splice effect (max delta 0.048). Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not covered by the VCEP PP3 (missense / single-aa in-frame deletion / splice) rules.
  • SpliceAI max delta score 0.048 predicts no splicing impact.
  • REVEL/BayesDel are not computed for non-SNV variants.
Sources
cspec ↗spliceai ↗vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP5 VCEPThe TP53 VCEP marks PP5 as 'Not Applicable for this VCEP' (recommended not for use by the ClinGen SVI VCEP Review Committee). Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies PP5 as not for use.
Sources
cspec ↗
BP1 VCEPThe TP53 VCEP marks BP1 as Not Applicable (truncating variants account for only a portion of disease-causing TP53 variants). Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies BP1 as Not Applicable.
Sources
cspec ↗
BP2 VCEPThe TP53 VCEP marks BP2 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies BP2 as Not Applicable.
Sources
cspec ↗
BP3 VCEPThe TP53 VCEP marks BP3 as Not Applicable (in-frame deletion/insertion in a repetitive region without known function); this is a frameshift. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies BP3 as Not Applicable.
Sources
cspec ↗
BP4 N/AThe TP53 VCEP BP4 in-silico rules apply only to missense, single-amino-acid in-frame deletion, synonymous, and intronic variants; this is a frameshift, and SpliceAI predicts no splice impact (max delta 0.048). Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not covered by the VCEP BP4 rules.
  • SpliceAI max delta 0.048 predicts no splicing impact.
Sources
cspec ↗spliceai ↗vcep_pp3_bp4_codes
BP5 VCEPThe TP53 VCEP marks BP5 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies BP5 as Not Applicable.
Sources
cspec ↗
BP6 VCEPThe TP53 VCEP marks BP6 as 'Not Applicable for this VCEP' (recommended not for use by the ClinGen SVI VCEP Review Committee). Details ▾Hide ▴
Evidence considered
  • TP53 VCEP specifies BP6 as not for use.
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants without splicing impact; this is a frameshift deletion. Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not a synonymous/intronic variant.
Sources
cspec ↗spliceai ↗
PS5 N/APS5 is not a standard ACMG/AMP criterion and is not present in the TP53 VCEP framework. Details ▾Hide ▴
Evidence considered
  • No PS5 criterion exists in the TP53 VCEP specifications.
Sources
cspec ↗

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.599_600del
Protein (HGVS p.)
NP_000537.3:p.(Asn200IlefsTer8)
GRCh38
chr17:7674930 AAT>A
GRCh37
chr17:7578248 AAT>A

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…
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 +24 bp
0.048
SpliceAI acceptor gainat +70 bp
0.001
SpliceAI donor lossat -71 bp
0.023
SpliceAI donor gainat -134 bp
0.003
Pangolin splice lossmagnitude shown
-0.144
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AThe TP53 VCEP PP3 in-silico rules apply only to missense variants, single-amino-acid in-frame deletions, and splice variants; this is a frameshift, and SpliceAI predicts no splice effect (max delta 0.048). Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not covered by the VCEP PP3 (missense / single-aa in-frame deletion / splice) rules.
  • SpliceAI max delta score 0.048 predicts no splicing impact.
  • REVEL/BayesDel are not computed for non-SNV variants.
Sources
cspec ↗spliceai ↗vcep_pp3_bp4_codesvcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP4 N/AThe TP53 VCEP BP4 in-silico rules apply only to missense, single-amino-acid in-frame deletion, synonymous, and intronic variants; this is a frameshift, and SpliceAI predicts no splice impact (max delta 0.048). Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not covered by the VCEP BP4 rules.
  • SpliceAI max delta 0.048 predicts no splicing impact.
Sources
cspec ↗spliceai ↗vcep_pp3_bp4_codes
BP7 N/ABP7 applies to synonymous or intronic variants without splicing impact; this is a frameshift deletion. Details ▾Hide ▴
Evidence considered
  • Frameshift variant is not a synonymous/intronic variant.
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

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

  • A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
    Reports biophysical characterization of the p53-R337H tetramerization domain, showing pH-dependent destabilization of the mutant tetramer in adrenocortical carcinoma. NM_000546.6:c.599_600del was not identified in this paper.
    Does not name this variant
    PMID 11753428 ↗
  • Rescuing the function of mutant p53.
    Commentary on strategies to restore function of mutant p53, discussing p53 structure and cancer-associated mutations at the gene level. NM_000546.6:c.599_600del was not identified in this paper.
    Does not name this variant
    PMID 11900253 ↗
  • The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.
    Comprehensive missense mutation library study of the p53 oligomerization domain assessing transcriptional activity of 184 mutant p53s. NM_000546.6:c.599_600del was not identified in this paper.
    Does not name this variant
    PMID 16007150 ↗
  • High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
    Reports a high incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer by sequencing TP53 exons 2-9. The specific variant NM_000546.6:c.599_600del was not identified in this paper.
    Does not name this variant
    PMID 19336573 ↗
  • Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
    Prognostic study of truncating TP53 mutations in head and neck squamous cell carcinoma, finding truncating mutations associate with worse overall and progression-free survival. The specific variant NM_000546.6:c.599_600del was not identified in this paper.
    Does not name this variant
    PMID 21467160 ↗

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 0.048 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

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 = 0.05).

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.