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TP53c.1154delUncertain significance
Print report
Variant interpretation report

TP53 c.1154del, p.(Phe385SerfsTer37)

NM_000546.6:c.1154del NP_000537.3:p.(Phe385SerfsTer37) 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. 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
PVS1Moderate
PVS1 · moderate

Frameshift variant NM_000546.6:c.1154del (p.Phe385SerfsTer37) produces a premature termination codon at position 421, downstream of the natural stop codon at p.Asp393. Per the TP53 VCEP PVS1 flowchart, frameshift-induced PTC downstream of the natural stop codon is assigned PVS1_Moderate.

PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 6.2e-07 (1/1,614,126 alleles; 0.000062%), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. The highest subpopulation frequency is South Asian at 0.0011% (1/91,080), below the 0.004% threshold for multiple alleles within a genetic ancestry group. Absent from gnomAD v2.1 and gnomAD-Canada.

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: PVS1 moderate (+2) + PM2 supporting (+1) = 3 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
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53389349, n = 2 times).

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.

28 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 14 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

PVS1_Moderate applied: frameshift variant c.1154del (p.Phe385SerfsTer37) produces a premature termination codon downstream of the natural stop codon, qualifying for PVS1 at moderate strength per the TP53 VCEP PVS1 flowchart.

PM2_Supporting applied: variant is extremely rare in population databases (gnomAD v4.1 AF 6.2e-07, 1/1,614,126 alleles), well below the VCEP PM2_Supporting threshold of 0.003%.

Total pathogenic points: 3 (PVS1_Moderate = 2, PM2_Supporting = 1). Per Tavtigian point-based system adopted by TP53 VCEP v2.4, a score of 3 falls in the range -1 to 5, consistent with Uncertain Significance.

Functional evidence could not be applied: the TP53 VCEP functional worksheet covers missense variants and small in-frame deletions only; frameshift variants are not represented.

This variant has been observed in somatic cancers (COSMIC, n=2) and is absent from ClinVar. OncoKB classifies it as Likely Oncogenic with a Likely Loss-of-function biological effect.

Met · 2

PVS1 ModerateFrameshift variant NM_000546.6:c.1154del (p.Phe385SerfsTer37) produces a premature termination codon at position 421, downstream of the natural stop codon at p.Asp393. Per the TP53 VCEP PVS1 flowchart, frameshift-induced PTC downstream of the natural stop codon is assigned PVS1_Moderate. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion in exon 11 (c.1101-*1188)
  • PTC at codon 421
  • downstream of natural stop at codon 394
  • TP53 VCEP PVS1 flowchart assigns PVS1_Moderate for frameshift-induced PTC downstream of natural stop codon
Sources
vcep_pvs1_flowchartcspec ↗
PM2 SupportingThis variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 6.2e-07 (1/1,614,126 alleles; 0.000062%), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. The highest subpopulation frequency is South Asian at 0.0011% (1/91,080), below the 0.004% threshold for multiple alleles within a genetic ancestry group. Absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/1
  • 614
  • 126 alleles (AF 6.2e-07)
  • South Asian subpopulation: 1/91
  • 080 (AF 1.1e-05 = 0.0011%)
  • Absent from gnomAD v2.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v4 ↗gnomad_v2 ↗cspec ↗

Not met · 12 · evaluated, threshold not reached

PS1 No same-position nucleotide variant has been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. PS1 requires a different nucleotide change at the same position with a previously established VCEP P/LP classification, which is not available for c.1154del. Details ▾Hide ▴
Evidence considered
  • PM5 candidates search confirmed no missense-like comparator at this position
Still missing
  • No VCEP-classified comparator variant at nucleotide position c.1154
Sources
cspec ↗pm5_candidates
PS2 No de novo observation data are available for this variant. No trio or parentage-confirmed studies have been reported. Details ▾Hide ▴
Still missing
  • No de novo or family studies available for this variant
PS3 The TP53 VCEP functional assay worksheet (Supplementary Table S3) covers missense variants and small in-frame deletions only; frameshift variants including c.1154del are not represented. No variant-specific functional data from the literature was identified for NM_000546.6:c.1154del. The five OncoKB-associated publications discuss TP53 at the gene level but none mention this specific variant. Details ▾Hide ▴
Evidence considered
  • VCEP Functional-worksheet.xlsx contains missense substitutions at Phe385 (F385C/I/L/S/V/Y) but no frameshift entries
  • Frameshift variants are outside the scope of VCEP functional codes
Still missing
  • No variant-specific functional assay data available
  • No systematic range characterization spanning codon 385 for frameshift variants
Sources
vcep_functional_worksheetoncokb ↗
PS4 No case-control data or proband counts with Li-Fraumeni syndrome-associated cancers are available. Proband point tally cannot be performed without clinical phenotype data. Details ▾Hide ▴
Still missing
  • No proband cancer phenotype data available for PS4 point tally
PM1 The TP53 VCEP restricts PM1 to missense variants at codons 175, 245, 248, 249, 273, 282 (moderate), or cancerhotspots.org with sufficient somatic occurrences. This is a frameshift deletion at codon 385, not a missense variant in a VCEP-defined hotspot codon. Details ▾Hide ▴
Evidence considered
  • VCEP PM1 rule is restricted to missense variants at specific hotspot codons
  • c.1154del is a frameshift
  • not a missense variant
  • Cancerhotspots.org: no statistically significant hotspot at this residue
Sources
cspec ↗
PP1 No cosegregation data are available. No family studies with meioses counts have been reported for this variant. Details ▾Hide ▴
Still missing
  • No family segregation studies available
PP4 No patient phenotype data or variant allele fraction (VAF) information is available. VCEP PP4 requires observation of the variant with VAF 5-35% in patients with Li-Fraumeni syndrome phenotype. Details ▾Hide ▴
Still missing
  • No patient phenotype or VAF data available
BA1 The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), well below the VCEP BA1 threshold of 0.1% (FAF ≥0.001). Only 1 allele observed; BA1 requires ≥2 alleles in a continental subpopulation with ≥2,000 alleles tested. Details ▾Hide ▴
Evidence considered
  • South Asian AF = 0.0011% (1/91
  • 080)
  • below BA1 threshold of 0.1%
  • Single allele observed
  • BA1 requires ≥2 alleles
Sources
gnomad_v4 ↗cspec ↗
BS1 The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), below the VCEP BS1 threshold of 0.03% (FAF ≥0.0003). Only 1 allele observed; BS1 requires ≥2 alleles in a continental subpopulation. Details ▾Hide ▴
Evidence considered
  • South Asian AF = 0.0011% (1/91
  • 080)
  • below BS1 threshold of 0.03%
  • Single allele observed
  • BS1 requires ≥2 alleles
Sources
gnomad_v4 ↗cspec ↗
BS2 No data on unrelated females who have reached at least 60 years of age without cancer. VCEP BS2 requires ≥2 such individuals from a single source. Details ▾Hide ▴
Still missing
  • No data on healthy older females carrying this variant
BS3 The TP53 VCEP functional assay worksheet covers missense variants and small in-frame deletions only. This frameshift variant is not represented. No variant-specific benign functional data identified in the literature. Details ▾Hide ▴
Evidence considered
  • VCEP Functional-worksheet.xlsx does not include frameshift variants
  • Missense substitutions at Phe385 show BS3 (functional) for most variants
  • but this does not extend to the frameshift
Still missing
  • No functional data for this specific frameshift variant
Sources
vcep_functional_worksheet
BS4 No segregation data available. VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. Details ▾Hide ▴
Still missing
  • No family segregation studies available
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 VCEPPM4 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 under TP53 VCEP applies only to missense variants at an amino acid residue where a different missense P/LP variant has been identified. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴
Evidence considered
  • PM5 candidates search confirmed variant is not missense-like
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is explicitly marked as Not Applicable by the TP53 VCEP (combined with PS2). Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

PP3 N/ATP53 VCEP PP3 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • Frameshift deletion not covered by VCEP in silico rules
  • SpliceAI max delta = 0.00 (no predicted splicing effect)
Sources
vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7spliceai ↗
PP5 VCEPPP5 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPBP3 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ATP53 VCEP BP4 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion not covered by VCEP in silico rules
Sources
vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5 VCEPBP5 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is explicitly marked as Not Applicable by the TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 under TP53 VCEP applies to synonymous (silent) and intronic variants only. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANot in the assessment list for this adjudication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.1154del
Protein (HGVS p.)
NP_000537.3:p.(Phe385SerfsTer37)
GRCh38
chr17:7669636 GA>G
GRCh37
chr17:7572954 GA>G
COSMIC
COSV53389349

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 1 / 1,614,126 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,614,126 alleles · 0 hom
South Asian1 / 91,080 1.1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.1953e-07; MAF= 0.00006%, 1/1614126 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09794e-05; MAF= 0.00110%, 1/91080 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ATP53 VCEP PP3 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • Frameshift deletion not covered by VCEP in silico rules
  • SpliceAI max delta = 0.00 (no predicted splicing effect)
Sources
vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7spliceai ↗
BP4 N/ATP53 VCEP BP4 rules cover missense variants (BayesDel), single amino acid in-frame deletions (BayesDel), and splice variants (SpliceAI). This is a frameshift deletion, not covered by VCEP in silico codes. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion not covered by VCEP in silico rules
Sources
vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7 N/ABP7 under TP53 VCEP applies to synonymous (silent) and intronic variants only. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

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

  • A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
    Reports on the R337H mutation in the p53 tetramerization domain and its pH-dependent destabilization in adrenocortical carcinoma. NM_000546.6:c.1154del was not identified in this paper.
    Does not name this variant
    PMID 11753428 ↗
  • Rescuing the function of mutant p53.
    Review article discussing strategies for rescuing mutant p53 function through small molecules and peptides. NM_000546.6:c.1154del 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 analysis of the p53 oligomerization domain examining 184 mutant p53 transcriptional activities. This study evaluated missense substitutions only; the frameshift variant NM_000546.6:c.1154del was not included.
    Does not name this variant
    PMID 16007150 ↗
  • High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
    Reports high incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Discusses truncating TP53 mutations as a class but NM_000546.6:c.1154del specifically was not identified in the abstract.
    Does not name this variant
    PMID 19336573 ↗
  • Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
    Reports prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma. Discusses truncating mutations as a class but NM_000546.6:c.1154del specifically was not identified in the abstract.
    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 1 / 1,614,126 recorded alleles 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

This variant is present in gnomAD v4.1 (AF= 6.1953e-07; MAF= 0.00006%, 1/1614126 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09794e-05; MAF= 0.00110%, 1/91080 alleles, homozygotes = 0).

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 previously been reported in somatic cancers (COSMIC; COSV53389349, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.