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TP53c.431_436delUncertain significance
Print report
Variant interpretation report

TP53 c.431_436del, p.(Gln144_Trp146delinsArg)

NM_000546.6:c.431_436del NP_000537.3:p.(Gln144_Trp146delinsArg) View identifiers
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.

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 v2.4.0. 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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000546.6:c.431_436del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies the VCEP PM2_Supporting rule requiring an allele frequency below 0.00003 (0.003%).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 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.

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
COSMIC ↗Cancer Hotspots ↗
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: 1 met · 6 not met · 8 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000546.6:c.431_436del (p.Gln144_Trp146delinsArg) is a 6-bp in-frame deletion in exon 5 of TP53, removing two amino acids (Q144 and W146) in the DNA-binding core domain L2 loop region and inserting arginine.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2_Supporting (allele frequency < 0.003%).

The variant has not been reported in ClinVar and has not been observed in COSMIC.

SpliceAI predicts no splicing impact (max delta score = 0.00).

The variant is not covered by the VCEP PVS1 framework (in-frame deletion, not a null variant), nor by VCEP PP3/BP4 in silico rules (multi-amino-acid deletion, not a missense or single-AA deletion).

No variant-specific functional assay data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) are available; the VCEP Functional worksheet does not contain this variant. OncoKB infers a Likely Loss-of-function but this is a somatic curation and not a direct germline functional assay.

No proband data, segregation data, de novo observations, or cancer-phenotype data were available for this variant.

Only one criterion met: PM2_Supporting. All other applicable criteria are either not met, not assessed due to absent data, or not applicable per VCEP specifications.

Met · 1

PM2 SupportingNM_000546.6:c.431_436del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies the VCEP PM2_Supporting rule requiring an allele frequency below 0.00003 (0.003%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PS1 VCEP PS1 requires a same-residue missense variant previously classified as pathogenic or likely pathogenic by TP53 VCEP specifications. No comparator variant at residues 144-146 was identified with a VCEP classification. Details ▾Hide ▴
Evidence considered
  • No same-residue VCEP-classified pathogenic comparator found for this deletion variant
PP3 This variant is a 2-amino-acid in-frame deletion, which is not covered by the VCEP PP3 rules. VCEP PP3 addresses missense variants (requiring aGVGD and BayesDel thresholds), single amino acid in-frame deletions (requiring BayesDel ≥ 0.16), and exonic/intronic variants with predicted splice effects (SpliceAI ≥ 0.2). SpliceAI max delta score is 0.00. No BayesDel score is available for this multi-AA deletion type. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no predicted splice effect)
  • Not a single amino acid deletion
  • not covered by VCEP PP3 in silico framework
Still missing
  • No in silico tool calibrated for multi-amino-acid in-frame deletions under VCEP framework
Sources
spliceai ↗vcep_pp3_bp4_codes
BA1 VCEP BA1 requires a filtering allele frequency ≥ 0.001 (0.1%) in a gnomAD continental subpopulation. The variant is absent from all gnomAD populations. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • BA1 threshold not reached
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEP BS1 requires a filtering allele frequency ≥ 0.0003 (0.03%) but < 0.001 in a gnomAD continental subpopulation. The variant is absent from all gnomAD populations. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • BS1 threshold not reached
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 This is a 2-amino-acid in-frame deletion, which is not covered by the VCEP BP4 rules. VCEP BP4 addresses missense variants (BayesDel ≤ -0.008 and SpliceAI < 0.2), single amino acid in-frame deletions (BayesDel < 0.16 and SpliceAI < 0.2), and silent/intronic variants (SpliceAI ≤ 0.1). SpliceAI max delta is 0.00, but the variant type is outside the scope of the VCEP BP4 framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00
  • not a variant type covered by VCEP BP4
Still missing
  • No in silico tool calibrated for multi-amino-acid in-frame deletions under VCEP BP4 framework
Sources
spliceai ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no variant-specific publications were identified. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no external classification available
Sources
clinvar ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo observation data available for this variant. VCEP PS2 point-based scoring requires proband-level cancer data. Details ▾Hide ▴
Still missing
  • No proband phenotype or de novo data available
PS3 This 2-amino-acid in-frame deletion (p.Gln144_Trp146delinsArg) is not listed in the VCEP Functional worksheet (Supplementary Table S3), which covers single amino acid substitutions and single amino acid deletions. No variant-specific functional assay data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) was identified for this specific variant. OncoKB annotation of Likely Loss-of-function is a curated inference, not direct functional assay data. Details ▾Hide ▴
Evidence considered
  • Variant not found in Functional-worksheet.xlsx (S3)
  • no Kotler et al. data for this specific 2-AA deletion
  • OncoKB: Likely Oncogenic / Likely Loss-of-function (somatic curation
  • not germline functional assay)
Still missing
  • No variant-specific functional assay data from eligible studies
Sources
vcep_functional_worksheetoncokb ↗
PS4 No proband data available. The variant is absent from ClinVar. VCEP PS4 point-based scoring requires proband-level cancer phenotype data. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no proband counts or cancer phenotype data available
Still missing
  • No proband observations available for PS4 point scoring
Sources
clinvar ↗
PP1 No cosegregation data available. VCEP PP1 requires observation of cosegregation in 3 or more meioses across families. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 VCEP PP4 requires observation of the variant with a variant allele fraction (VAF) of 5-35%. No VAF data or phenotype data are available for this variant. Details ▾Hide ▴
Still missing
  • No VAF or phenotype data available
BS2 VCEP BS2 requires observation of the variant in unrelated females who have reached at least 60 years of age without cancer. No such data are available. Details ▾Hide ▴
Still missing
  • No data on cancer-free females ≥ 60 years of age carrying this variant
BS3 This 2-amino-acid in-frame deletion is not listed in the VCEP Functional worksheet. No variant-specific functional data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) are available. The VCEP BS3 rules require functional assay outcomes (functional/partially functional/non-functional on Kato data and LOF status across additional assays) that are not available for this variant. Details ▾Hide ▴
Evidence considered
  • Variant not present in Functional-worksheet.xlsx Supplementary Table S3
Still missing
  • No variant-specific functional assay data from eligible studies
Sources
vcep_functional_worksheet
BS4 VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. No segregation data are available. Details ▾Hide ▴
Still missing
  • No family segregation data available
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000546.6:c.431_436del is a 6-bp in-frame deletion resulting in p.(Gln144_Trp146delinsArg). The TP53 VCEP PVS1 flowchart applies exclusively to null variants (nonsense, frameshift, canonical splice, initiation codon, CNVs). In-frame deletions are not covered by the PVS1 decision tree. Details ▾Hide ▴
Evidence considered
  • c.431_436del is an in-frame deletion in exon 5
  • resulting in substitution of Gln144-Trp146 with Arg — not a null variant
Sources
vcep_pvs1_flowchart
PM1 N/AVCEP PM1 applies to missense variants at codons 175, 245, 248, 249, 273, 282, or germline missense variants with ≥2 somatic occurrences for the same amino acid change at cancerhotspots.org. This variant is an in-frame deletion, not a missense substitution. Details ▾Hide ▴
Evidence considered
  • c.431_436del is an in-frame deletion at residues 144-146
  • not a missense variant at PM1-designated codons
PM4 VCEPVCEP TP53 specifications mark PM4 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AVCEP PM5 applies to missense variants at the same amino acid residue where another missense variant has been classified as pathogenic or likely pathogenic. The assessed variant is an in-frame deletion (not a missense change), and the pm5_candidates analysis confirmed it is not eligible for classic same-residue missense PM5. Details ▾Hide ▴
Evidence considered
  • In-frame deletion
  • not a missense variant
  • no eligible PM5 comparator
Sources
pm5_candidates
PM6 VCEPVCEP TP53 specifications mark PM6 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPVCEP TP53 specifications mark PP2 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPVCEP TP53 specifications mark PP5 as Not Applicable; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPVCEP TP53 specifications mark BP1 as Not Applicable; this rule does not apply to TP53 because truncating variants account for only a portion of disease-causing variants. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPVCEP TP53 specifications mark BP2 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPVCEP TP53 specifications mark BP3 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPVCEP TP53 specifications mark BP5 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPVCEP TP53 specifications mark BP6 as Not Applicable for this gene. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVCEP BP7 applies to synonymous (silent) variants or intronic variants outside canonical splice sites. This variant is an in-frame deletion in the coding region. Details ▾Hide ▴
Evidence considered
  • In-frame coding deletion
  • not a synonymous or intronic variant

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.431_436del
Protein (HGVS p.)
NP_000537.3:p.(Gln144_Trp146delinsArg)
GRCh38
chr17:7675175 CACAGCT>C
GRCh37
chr17:7578493 CACAGCT>C

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

Pangolin splice lossmagnitude shown
-0.060
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 This variant is a 2-amino-acid in-frame deletion, which is not covered by the VCEP PP3 rules. VCEP PP3 addresses missense variants (requiring aGVGD and BayesDel thresholds), single amino acid in-frame deletions (requiring BayesDel ≥ 0.16), and exonic/intronic variants with predicted splice effects (SpliceAI ≥ 0.2). SpliceAI max delta score is 0.00. No BayesDel score is available for this multi-AA deletion type. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no predicted splice effect)
  • Not a single amino acid deletion
  • not covered by VCEP PP3 in silico framework
Still missing
  • No in silico tool calibrated for multi-amino-acid in-frame deletions under VCEP framework
Sources
spliceai ↗vcep_pp3_bp4_codes
BP4 This is a 2-amino-acid in-frame deletion, which is not covered by the VCEP BP4 rules. VCEP BP4 addresses missense variants (BayesDel ≤ -0.008 and SpliceAI < 0.2), single amino acid in-frame deletions (BayesDel < 0.16 and SpliceAI < 0.2), and silent/intronic variants (SpliceAI ≤ 0.1). SpliceAI max delta is 0.00, but the variant type is outside the scope of the VCEP BP4 framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00
  • not a variant type covered by VCEP BP4
Still missing
  • No in silico tool calibrated for multi-amino-acid in-frame deletions under VCEP BP4 framework
Sources
spliceai ↗
BP7 N/AVCEP BP7 applies to synonymous (silent) variants or intronic variants outside canonical splice sites. This variant is an in-frame deletion in the coding region. Details ▾Hide ▴
Evidence considered
  • In-frame coding deletion
  • not a synonymous or intronic variant

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

  • Rescuing the function of mutant p53.
    Review article discussing p53 structure, mutation classes, thermodynamic stability, and drug rescue strategies for mutant p53. Describes six mutation hotspots (R175, G245, R248, R249, R273, R282) and functional classification of p53 missense mutations. NM_000546.6:c.431_436del was not identified in this paper.
    Does not name this variant
    PMID 11900253 ↗
  • Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.
    Original crystal structure report of the human p53 core domain (residues 94-312) bound to DNA, solved at 2.2 Å resolution. Describes the DNA-binding surface including the loop-sheet-helix (LSH) motif, L2 and L3 loops, zinc-binding site, and key DNA-contact residues (R248, R273, R280, K120). NM_000546.6:c.431_436del was not identified in this paper.
    Does not name this variant
    PMID 8023157 ↗

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

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.