About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.490A>G, p.(Lys164Glu)
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.
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
In TP53 functional studies, this variant was non-functional in the Kato transactivation assay and showed loss of function across other eligible assays in the TP53 VCEP functional worksheet, supporting PS3 at strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003. The single observed allele is in Ashkenazi Jewish, a founder-influenced population excluded by the TP53 VCEP population rule.
PP3Supporting
PP3 · supporting
TP53 VCEP bioinformatic tables assign PP3 to c.490A>G. BayesDel is 0.557217, above the TP53 pathogenic threshold of 0.16, and REVEL is 0.875, supporting a damaging effect; SpliceAI shows no splice impact (max delta score 0.00).
PP5Supporting
PP5 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) + PP5 supporting (+1) = 7 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,174 alleles
gnomAD v4.1: 1 / 1,614,174 alleles. Recorded AF 6.19512e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Uncertain significance · 1 Likely pathogenic · 1 Pathogenic.
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
34 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52728094, n = 34 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.
28 criteria with recorded statuses: 4 met · 6 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The TP53 c.490A>G (p.Lys164Glu) variant has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen TP53 Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003.
In published TP53 functional studies summarized by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function across other eligible assays, supporting PS3 at strong strength.
TP53 VCEP computational tables assign PP3 to this missense change; BayesDel is 0.557217 and REVEL is 0.875, while SpliceAI predicts no significant splice impact (max delta score 0.00).
No criteria match.
Met · 4
PS3 StrongIn TP53 functional studies, this variant was non-functional in the Kato transactivation assay and showed loss of function across other eligible assays in the TP53 VCEP functional worksheet, supporting PS3 at strong strength. Details ▾Hide ▴
Rule
Non-functional on Kato data and loss of function by the majority of other eligible assays
Evidence considered
- TP53 VCEP functional worksheet row for K164E: NA / Non-functional / LOF / LOF / LOF / NA / PS3.
- ClinVar cites the core TP53 functional studies.
Sources
PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesclinvar ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003. The single observed allele is in Ashkenazi Jewish, a founder-influenced population excluded by the TP53 VCEP population rule. Details ▾Hide ▴
Rule
TP53 PM2_Supporting: AF < 0.00003, with founder-influenced populations excluded
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 1 allele total
- AF 6.195118989650434e-07.
- Best observed subpopulation is Ashkenazi Jewish with 1 allele.
Sources
PP3 SupportingTP53 VCEP bioinformatic tables assign PP3 to c.490A>G. BayesDel is 0.557217, above the TP53 pathogenic threshold of 0.16, and REVEL is 0.875, supporting a damaging effect; SpliceAI shows no splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 missense PP3_Supporting: aGVGD class C25-C55 with BayesDel >= 0.16
Evidence considered
- TP53 VCEP PP3-BP4 spreadsheet row: c.490A>G / p.Lys164Glu / Class C55 / 0.557217 / PP3.
- REVEL score 0.875.
- SpliceAI max delta score 0.00.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
Not met · 6 · evaluated, threshold not reached
PS1 No different nucleotide change producing the same p.Lys164Glu amino acid substitution was identified in the reviewed ClinVar evidence, so PS1 is not met. Details ▾Hide ▴
PM5 A review of same-residue comparator evidence did not identify a different TP53 missense variant at Lys164 previously established as pathogenic or likely pathogenic under the TP53 framework, so PM5 is not met. Details ▾Hide ▴
Rule
TP53 PM5 requires a different pathogenic or qualifying likely pathogenic missense variant at the same residue
Evidence considered
- PM5 candidate artifact did not yield a usable pathogenic missense comparator.
- Reviewed ClinVar same-residue missense entries at codon 164.
Sources
BA1 Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BA1 threshold of 0.001. The only observed gnomAD v4.1 allele yields a total AF of 6.20e-07. Details ▾Hide ▴
Rule
TP53 BA1 requires founder-excluded FAF >= 0.001
Evidence considered
- gnomAD v4.1 total AF 6.195118989650434e-07 with 1 allele.
Sources
BS1 Available population data do not show a qualifying founder-excluded continental frequency at or above the TP53 BS1 threshold of 0.0003. The observed gnomAD v4.1 total AF is 6.20e-07. Details ▾Hide ▴
Rule
TP53 BS1 requires founder-excluded FAF >= 0.0003 and < 0.001
Evidence considered
- gnomAD v4.1 total AF 6.195118989650434e-07 with 1 allele.
Sources
BS3 Available TP53 functional evidence does not show retained or partially retained wild-type function. Instead, the TP53 VCEP functional worksheet classifies p.K164E as PS3 based on non-functional and loss-of-function assay results, so BS3 is not met. Details ▾Hide ▴
Rule
BS3 requires retained or partially retained function without evidence of loss of function across eligible assays
Evidence considered
- TP53 VCEP functional worksheet row for K164E assigns PS3
- not BS3.
Sources
PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
BP4 Benign computational evidence is not supported. BayesDel is 0.557217, which is not below the TP53 BP4 thresholds, the TP53 VCEP precomputed assignment for this variant is PP3 rather than BP4, and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 BP4 missense rule requires BayesDel < 0.16 with no splice effect; BP4_Moderate requires BayesDel <= -0.008
Evidence considered
- TP53 VCEP PP3-BP4 spreadsheet assigns PP3.
- BayesDel score 0.557217.
- SpliceAI max delta score 0.00.
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo observation with the TP53 VCEP point-based case information was identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
TP53 PS2 point thresholds: Supporting 1 point, Moderate 2-3, Strong 4-7, Very Strong >=8
Evidence considered
- Reviewed ClinVar evidence for de novo information.
- Applied TP53 VCEP PS2 point framework.
Still missing
- Proband-level de novo data with maternity/paternity status were not available.
- No TP53 PS2 point total could be calculated.
Sources
PS4 Although this variant has been reported in ClinVar, no proband-level Li-Fraumeni syndrome point data were identified to calculate the TP53 PS4 score, so PS4 cannot be assessed. Details ▾Hide ▴
Rule
TP53 PS4 point thresholds: Supporting 1-1.5 points, Moderate 2-3.5, Strong 4-7.5, Very Strong >=8
Evidence considered
- Reviewed ClinVar evidence for affected-case context.
- Applied TP53 VCEP PS4 point framework.
Still missing
- No qualifying proband counts or cancer-point totals were available.
- No TP53 PS4 point total could be calculated.
Sources
PM1 Cancer Hotspots review for residue Lys164 was flagged as uncertain and did not verify a residue-specific or exact amino-acid-change count in cancerhotspots.org, so the TP53 PM1 threshold cannot be confirmed. Details ▾Hide ▴
Rule
TP53 PM1 requires specified hotspot codons or a verified cancerhotspots.org count for the same amino acid change
Evidence considered
- Cancer Hotspots capture was marked uncertain and needs human review.
Still missing
- A verified cancerhotspots.org count for p.Lys164Glu is still needed.
- Residue-level hotspot status was not cleanly captured from the available hotspot review.
Sources
PP1 No segregation data were identified to count informative meioses, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
TP53 PP1 thresholds: Supporting 3-4 meioses, Moderate 5-6, Strong >=7 across >1 family
Evidence considered
- Reviewed available ClinVar evidence for family data.
- Applied TP53 VCEP PP1 meiosis thresholds.
Still missing
- No pedigree-level meiosis count was available.
- No qualifying cosegregation data were identified.
Sources
PP4 No qualifying low-VAF constitutional mosaic observation data were identified, so the TP53-specific PP4 rule cannot be assessed. Details ▾Hide ▴
Rule
TP53 PP4 requires variant observations with qualifying VAF patterns
Evidence considered
- Applied TP53 VCEP PP4 requirements.
Still missing
- No blood variant allele fraction data were available.
- No independent low-VAF constitutional observations were identified.
Sources
BS2 No data were identified showing unrelated cancer-free females aged at least 60 years from a single source who carry this variant, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
TP53 BS2 thresholds are based on unrelated cancer-free females >=60 years from a single source
Evidence considered
- Applied TP53 VCEP BS2 requirements.
Still missing
- No qualifying unaffected-carrier series was available.
- Single-source carrier counts were not identified.
Sources
BS4 No lack-of-segregation data were identified in affected family members, so BS4 cannot be assessed. Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution, p.(Lys164Glu), rather than a nonsense, frameshift, canonical +/-1,2 splice, or copy-number loss variant, and SpliceAI predicts no splice effect (max delta score 0.00). The TP53-specific PVS1 framework therefore does not apply. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 null-variant framework
Evidence considered
- Variant is a missense change.
- SpliceAI max delta score is 0.00.
- TP53 VCEP PVS1 guidance is limited to null/splice/CNV contexts.
Sources
PM3 VCEPPM3 is not applicable in the TP53 VCEP framework for this disorder context. Details ▾Hide ▴
PM4 VCEPPM4 is not applicable because this variant is a missense substitution and the TP53 VCEP does not use PM4 for this context. Details ▾Hide ▴
PM6 VCEPPM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable because this is not an in-frame indel in a repetitive region and the TP53 VCEP does not use BP3 here. Details ▾Hide ▴
BP5 VCEPBP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP6 VCEPBP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or qualifying intronic. Details ▾Hide ▴
Evidence considered
- Variant consequence is missense p.(Lys164Glu).
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.490A>G
- Protein (HGVS p.)
- NP_000537.3:p.(Lys164Glu)
- GRCh38
- chr17:7675122 T>C
- GRCh37
- chr17:7578440 T>C
- ClinVar
- 246416
- COSMIC
- COSV52728094
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
1 / 1,614,174 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,174 alleles · 0 hom
| Ashkenazi Jewish1 / 29,602 | 3.4e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19512e-07; MAF= 0.00006%, 1/1614174 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.875
- BayesDel
- 0.557
How the predictions were used
PP3 SupportingTP53 VCEP bioinformatic tables assign PP3 to c.490A>G. BayesDel is 0.557217, above the TP53 pathogenic threshold of 0.16, and REVEL is 0.875, supporting a damaging effect; SpliceAI shows no splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 missense PP3_Supporting: aGVGD class C25-C55 with BayesDel >= 0.16
Evidence considered
- TP53 VCEP PP3-BP4 spreadsheet row: c.490A>G / p.Lys164Glu / Class C55 / 0.557217 / PP3.
- REVEL score 0.875.
- SpliceAI max delta score 0.00.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
BP4 Benign computational evidence is not supported. BayesDel is 0.557217, which is not below the TP53 BP4 thresholds, the TP53 VCEP precomputed assignment for this variant is PP3 rather than BP4, and SpliceAI predicts no splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 BP4 missense rule requires BayesDel < 0.16 with no splice effect; BP4_Moderate requires BayesDel <= -0.008
Evidence considered
- TP53 VCEP PP3-BP4 spreadsheet assigns PP3.
- BayesDel score 0.557217.
- SpliceAI max delta score 0.00.
Sources
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or qualifying intronic. Details ▾Hide ▴
Evidence considered
- Variant consequence is missense p.(Lys164Glu).
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.875. BayesDel score = 0.557217.
6 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
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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. · 2003No paper-specific finding is recorded.
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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. · 2018No paper-specific finding is recorded.
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PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.Giacomelli AO et al. · 2018No paper-specific finding is recorded.
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PMID 27328919 ↗TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.No paper-specific finding is recorded.
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PMID 9699640 ↗Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,174 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
3 Uncertain significance · 1 Likely pathogenic · 1 Pathogenic
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/246416/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578440-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675122-T-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.490A…
- OncoKB ↗www.oncokb.org/gene/TP53/K164E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104410677
- 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
This variant is present in gnomAD v4.1 (AF= 6.19512e-07; MAF= 0.00006%, 1/1614174 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 246416)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.875. BayesDel score = 0.557217.
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; COSV52728094, n = 34 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.