About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.520A>T, p.(Arg174Trp)
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 v2.4.0. 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: 1
Pathogenic criteria applied · 2
PS3Strong
PS3 · strong
TP53 VCEP Functional-worksheet (Supplementary Table S3) directly assigns PS3 to p.Arg174Trp (R174W). R174W is non-functional in the Kato et al. assay (PMID:12826609) and demonstrates loss of function across all other eligible functional assays (Giacomelli, Kotler, Kawaguchi), meeting the VCEP PS3 rule: non-functional on Kato data AND LOF by the majority of other eligible assays.
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns BP4 to c.520A>T. BayesDel score 0.149306 is < 0.16 and > -0.008 with aGVGD Class C35 (not C65), and SpliceAI max delta 0.0 confirms no predicted splicing impact, meeting the VCEP BP4_Supporting rule exactly.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + BP4 supporting (-1) = 4 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.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
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.
COSMIC
Cancer Hotspots
Somatic evidence
28 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52961532, n = 28 times).
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.
26 criteria with recorded statuses: 3 met · 6 not met · 7 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PS3 (strong) is met: R174W is non-functional in the Kato et al. assay and demonstrates loss of function across all eligible functional assays (Giacomelli, Kotler, Kawaguchi), per the TP53 VCEP Functional-worksheet pre-adjudicated assignment.
PM2_Supporting is met: the variant is absent from gnomAD v2.1 and v4.1, with an allele frequency below the VCEP threshold of 0.00003.
BP4_Supporting is met: the VCEP PP3-BP4-codes spreadsheet assigns BP4 to c.520A>T based on BayesDel score 0.149306 and SpliceAI max delta 0.0, indicating no predicted deleterious effect from in silico tools.
PM1 is not met: codon 174 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282), and the variant is not listed in cancerhotspots.org.
PS1 is not met: no alternate nucleotide change producing the same Arg174Trp amino acid substitution has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP.
PS4, PS2, PP1, PP4, BS2, and BS4 remain not assessed due to absence of proband-level clinical, segregation, or population phenotype data.
Applying the Tavtigian 2020 Bayesian point system: PS3 (+4) + PM2_Supporting (+1) + BP4_Supporting (-1) = 4 points. This falls within the VUS range (>= -1 and <= 5 points).
No criteria match.
Met · 3
PS3 StrongTP53 VCEP Functional-worksheet (Supplementary Table S3) directly assigns PS3 to p.Arg174Trp (R174W). R174W is non-functional in the Kato et al. assay (PMID:12826609) and demonstrates loss of function across all other eligible functional assays (Giacomelli, Kotler, Kawaguchi), meeting the VCEP PS3 rule: non-functional on Kato data AND LOF by the majority of other eligible assays. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet: R174W assigned PS3 (Kato: Non-functional
- Giacomelli: LOF
- Kotler: LOF
- Kawaguchi: LOF)
- PMID:20407015 (Jordan et al. 2010): R174W classified as FUNCTIONAL in yeast transactivation assay — retains transactivation from p21-5' and GADD45 REs
- indistinguishable from WT at high expression
- this in vitro transactivation result is noted but does not override the VCEP pre-adjudicated PS3 assignment based on the eligible functional assay panel.
Sources
PM2 SupportingVariant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingTP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns BP4 to c.520A>T. BayesDel score 0.149306 is < 0.16 and > -0.008 with aGVGD Class C35 (not C65), and SpliceAI max delta 0.0 confirms no predicted splicing impact, meeting the VCEP BP4_Supporting rule exactly. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.520A>T assigned BP4
- BayesDel: 0.149306 (between -0.008 and 0.16)
- aGVGD: Class C35 (not C65)
- SpliceAI max delta: 0.0 (no predicted splicing impact)
Sources
Not met · 6 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change producing the same amino acid change (Arg174Trp) previously classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. No such variant has been identified in the VCEP materials or ClinVar for this codon. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change producing Arg174Trp classified as P/LP by TP53 VCEP identified.
PM1 Codon 174 is not among the VCEP-defined TP53 hotspot codons (175, 245, 248, 249, 273, 282). The variant is not listed in cancerhotspots.org, so the supporting-level rule (2-9 somatic occurrences for same amino acid change) cannot be applied via that pathway. Although COSMIC reports 28 somatic occurrences and the residue is a statistically significant hotspot, the VCEP PM1 rule is restricted to the specified codons or cancerhotspots-listed variants. Details ▾Hide ▴
Evidence considered
- Codon 174 is adjacent to but outside the VCEP hotspot codon 175.
- COSMIC COSV52961532: 28 somatic occurrences.
- cancerhotspots.org: exact variant not listed.
PP3 TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns BP4 (not PP3) to c.520A>T. BayesDel score 0.149306 is below the 0.16 threshold required for PP3_Supporting (aGVGD Class C25-C55 AND BayesDel >= 0.16), and the variant is Class C35, not C65. SpliceAI max delta 0.0 confirms no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.520A>T assigned BP4
- BayesDel: 0.149306 (< 0.16)
- REVEL: 0.634
- SpliceAI max delta: 0.0
Sources
BA1 Variant is absent from gnomAD. Does not meet the TP53 VCEP BA1 threshold of filtering allele frequency >= 0.001 (0.1%) in any continental subpopulation. Details ▾Hide ▴
BS1 Variant is absent from gnomAD. Does not meet the TP53 VCEP BS1 threshold of filtering allele frequency >= 0.0003 (0.03%) in any continental subpopulation. Details ▾Hide ▴
BS3 TP53 VCEP Functional-worksheet assigns PS3 (not BS3) to R174W. The variant is non-functional in Kato assay with LOF across all eligible assays, which is the opposite of what BS3 requires (functional or partially functional with no LOF evidence). Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet: R174W assigned PS3
- Kato: Non-functional
- all other assays: LOF.
- BS3 would require functional on Kato AND no LOF by majority of assays (BS3_Strong) or partially functional on Kato AND no LOF by all assays (BS3_Supporting).
Sources
vcep_functional_worksheet
Not assessed · 7 · no assessment recorded
PS2 No proband data with de novo confirmation (maternity and paternity) or LFS cancer point scoring available for this variant. Details ▾Hide ▴
Still missing
- Proband-level de novo data with confirmed parentage and LFS cancer phenotypes required for PS2 point scoring.
PS4 No proband-level LFS cancer data available for PS4 point scoring. The ClinVar record (VCV000964680) contains a single submission classified as Uncertain Significance with no proband phenotype details. Details ▾Hide ▴
Evidence considered
- ClinVar VCV000964680: single submitter
- Uncertain Significance
- no proband phenotype data.
Still missing
- Proband-level cancer diagnoses required for LFS point scoring per the TP53 VCEP PS4-Points-Table.
Sources
PM5 PM5 requires a different missense variant at the same residue (Arg174) previously classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. While multiple other missense changes at codon 174 exist (R174G, R174K, R174M, R174S, R174T in PP3-BP4-codes; R174A/C/E/I/N/P/Q/V in Functional-worksheet), their VCEP clinical classifications (not just functional codes) are needed to apply PM5. Details ▾Hide ▴
Evidence considered
- Multiple missense variants at codon 174 identified in VCEP spreadsheets but VCEP clinical classifications not available for PM5 comparator assessment.
Still missing
- VCEP clinical classifications (P/LP/VUS/LB/B) for other missense variants at Arg174 required.
- If any R174 missense variant has been classified as P by VCEP
- PM5_Moderate (1 variant) or PM5_Strong (>=2 variants) would apply.
PP1 No cosegregation data available. The VCEP PP1 rule requires 3-4 meioses for Supporting, 5-6 for Moderate, or >=7 for Strong. Details ▾Hide ▴
Still missing
- Family cosegregation data required for PP1 assessment.
PP4 No variant allele fraction (VAF) data or specific phenotype observations available. The VCEP PP4 rule requires observation of the variant at VAF 5-35% (Supporting) or >=2 independent observations at VAF 5-25% (Moderate). Details ▾Hide ▴
Still missing
- Patient VAF data and phenotype details required for PP4 assessment.
BS2 No data available on unrelated females >=60 years of age without cancer. The VCEP BS2 rule requires 2-3 such individuals for Supporting, 4-7 for Moderate, or >=8 for Strong. Details ▾Hide ▴
Still missing
- Data on cancer-free females >=60 years of age from a single source required.
BS4 No segregation data available. The VCEP BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers. Details ▾Hide ▴
Still missing
- Family segregation data in LFS-affected families required.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice sites, CNVs); NM_000546.5:c.520A>T is a missense variant (p.Arg174Trp) and does not fall into any PVS1-eligible variant bucket per the TP53 VCEP PVS1 flowchart. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is explicitly marked as Not Applicable by the TP53 VCEP; de novo observations are assessed under the combined PS2 point-based rule instead. 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.
PP5 VCEPPP5 is explicitly marked as Not Applicable by the TP53 VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPBP1 is explicitly marked as Not Applicable by the TP53 VCEP; truncating variants account for only a portion of disease-causing variants in TP53. 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.
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 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. NM_000546.5:c.520A>T is a missense variant (p.Arg174Trp) and is not eligible for BP7. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a defined criterion in the TP53 VCEP framework. The VCEP uses a combined PS2/PM6 rule with point-based scoring for de novo observations; PS5 as a separate criterion is not recognized. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.520A>T
- Protein (HGVS p.)
- NP_000537.3:p.(Arg174Trp)
- GRCh38
- chr17:7675092 T>A
- GRCh37
- chr17:7578410 T>A
- ClinVar
- 964680
- COSMIC
- COSV52961532
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
- 0.634
- BayesDel
- 0.149
How the predictions were used
BP4 SupportingTP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns BP4 to c.520A>T. BayesDel score 0.149306 is < 0.16 and > -0.008 with aGVGD Class C35 (not C65), and SpliceAI max delta 0.0 confirms no predicted splicing impact, meeting the VCEP BP4_Supporting rule exactly. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.520A>T assigned BP4
- BayesDel: 0.149306 (between -0.008 and 0.16)
- aGVGD: Class C35 (not C65)
- SpliceAI max delta: 0.0 (no predicted splicing impact)
Sources
PP3 TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns BP4 (not PP3) to c.520A>T. BayesDel score 0.149306 is below the 0.16 threshold required for PP3_Supporting (aGVGD Class C25-C55 AND BayesDel >= 0.16), and the variant is Class C35, not C65. SpliceAI max delta 0.0 confirms no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.520A>T assigned BP4
- BayesDel: 0.149306 (< 0.16)
- REVEL: 0.634
- SpliceAI max delta: 0.0
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. NM_000546.5:c.520A>T is a missense variant (p.Arg174Trp) and is not eligible for BP7. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.634. BayesDel score = 0.149306.
9 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 20407015 ↗Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.Jordan JJ et al. · 2010 MayR174W classified as FUNCTIONAL in yeast transactivation assay. Retained transactivation from p21-5' and GADD45 response elements indistinguishable from wild-type p53 at high expression levels. Categorized among 12/50 breast cancer-associated missense mutants that appeared similar to WT in transactivation capacity.→ PS3 Names this variant
Source detail
R174W appeared similar to WT in their transactivation capacity
Location Table 1 (Functional Status column); Results, paragraph 7 ('R174W appeared similar to WT'); Figure 3 legend ('R174W and R267Q, do not affect the maximal level of transactivation'); Figure 4 legend ('A138V and R174W had similar transactivation potentials')
Context Isogenomic diploid yeast transactivation assay; GAL1-inducible p53 expression; ADE2 plate color assay and luciferase reporter; 11 human p53 target response elements assessed
Other recorded publications
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PMID 11900253 ↗Rescuing the function of mutant p53.Review article on rescuing mutant p53 function by small-molecule drugs. Discusses p53 structure, DNA binding, and mutation hotspots at a general gene level. No specific variant NM_000546.5:c.520A>T or p.Arg174Trp identified.Does not name this variant
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PMID 8023157 ↗Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.Crystal structure of a p53 tumor suppressor-DNA complex. Describes the core domain structure (residues 102-292). The abstract discusses mutation hotspots at the general structural level; no specific variant R174W mentioned.Does not name this variant
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PMID 12826609 ↗Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.Kato S et al. · 2003High-resolution missense mutation analysis of p53 tumor suppressor covering functional-structural relationships for 2,314 p53 mutants. This study provides the Kato assay data used by the TP53 VCEP Functional-worksheet for PS3/BS3 assignments. The specific variant R174W was not identified in the full-text search.Does not name this variant
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PMID 28826481 ↗A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer.Liu S et al. · 2017Comprehensive analysis of coregulator recruitment and androgen receptor function in prostate cancer. This study does not concern TP53 or p53 variants. No variant-specific p53 data present.Does not name this variant
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PMID 29979965 ↗A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.Kotler E et al. · 2018Systematic p53 mutation library linking differential functional impact to cancer mutation pattern. The abstract describes measurement of ~10,000 DBD p53 variants but does not mention R174W specifically. Full text not available for direct variant verification.Does not name this variant
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PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.Giacomelli AO et al. · 2018Systematic view of p53 function through loss-of-function screens in human cancer cell lines. This is the Giacomelli et al. study used by the TP53 VCEP Functional-worksheet. The specific variant R174W was not identified in the full-text search.Does not name this variant
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. Clinical practice guideline with no variant-level genetic data. No mention of TP53 variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. Methodological paper providing a general classification framework, not variant-specific data.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
1 Uncertain significance
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/variation/964680/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578410-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675092-T-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-7675092-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.520A…
- OncoKB ↗www.oncokb.org/gene/TP53/R174W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121487601
- 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 964680)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.634. BayesDel score = 0.149306.
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 previously been reported in somatic cancers (COSMIC; COSV52961532, n = 28 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.