About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.581T>G, p.(Leu194Arg)
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 the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, with a pre-assigned PS3 code. This supports a damaging effect on TP53 protein function.
PM2Supporting
PM2 · supporting
This variant is rare in population databases. In gnomAD v4.1 it is present in 1/1,614,188 alleles (AF 6.20e-07), and in gnomAD v2.1 it is present in 1/251,486 alleles (AF 3.98e-06), both below the TP53 PM2 threshold of 0.00003.
PP3Moderate
PP3 · moderate
In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate. BayesDel is 0.582962, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect rather than a splicing mechanism.
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 moderate (+2) + PP5 supporting (+1) = 8 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 / 1,614,188 alleles
gnomAD v4.1: 1 / 1,614,188 alleles. Recorded AF 6.19507e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97636e-06; MAF= 0.00040%, 1/251486 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 8 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
The TP53 c.581T>G (p.Leu194Arg; p.L194R) variant has curated somatic cancer literature in OncoKB and is reported in ClinVar as Pathogenic, including by the ClinGen TP53 Variant Curation Expert Panel.
This variant is rare in population databases, with 1/1614188 alleles in gnomAD v4.1 (AF 6.20e-07) and 1/251486 alleles in gnomAD v2.1 (AF 3.98e-06), which is below the TP53 PM2 threshold of 0.00003.
In the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, supporting PS3.
In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate; BayesDel is 0.582962, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect without evidence for a splice-based mechanism.
No criteria match.
Met · 4
PS3 StrongIn the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, with a pre-assigned PS3 code. This supports a damaging effect on TP53 protein function. Details ▾Hide ▴
Rule
TP53 VCEP PS3 Strong: non-functional on Kato and loss of function by the majority of other eligible assays.
Evidence considered
- Functional worksheet row: L194R | NA | Non-functional | LOF | LOF | LOF | NA | PS3.
- TP53 VCEP functional flowchart designates these assay patterns for PS3/BS3 application.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
PM2 SupportingThis variant is rare in population databases. In gnomAD v4.1 it is present in 1/1,614,188 alleles (AF 6.20e-07), and in gnomAD v2.1 it is present in 1/251,486 alleles (AF 3.98e-06), both below the TP53 PM2 threshold of 0.00003. Details ▾Hide ▴
Rule
TP53 VCEP PM2 Supporting: allele frequency < 0.00003 in a large population database.
Evidence considered
- gnomAD v4 total AF 6.195065258817436e-07.
- gnomAD v2 total AF 3.976364489474563e-06.
Sources
PP3 ModerateIn the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate. BayesDel is 0.582962, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect rather than a splicing mechanism. Details ▾Hide ▴
Rule
TP53 VCEP PP3 Moderate for missense variants with aGVGD C65 and BayesDel >= 0.16.
Evidence considered
- PP3-BP4 worksheet row: c.581T>G | p.Leu194Arg | Class C65 | 0.582962 | PP3_moderate | 0.13.
- REVEL score 0.933.
- SpliceAI max delta score 0.13.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
Not met · 6 · evaluated, threshold not reached
PVS1 This missense variant is not a nonsense, frameshift, canonical +/-1,2 splice, or other null variant, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.13). Available evidence does not support applying TP53-specific PVS1 to this variant. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 applies to null/splice categories defined in the TP53-specific flowchart; this variant does not meet those entry conditions.
Evidence considered
- TP53 is eligible for PVS1 in the gene-level framework.
- Variant-level PVS1 assessment places c.581T>G outside the default null-variant buckets.
- SpliceAI max delta score is 0.13.
Still missing
- RNA evidence showing a null-equivalent splicing effect was not identified.
Sources
PM1 Although this variant has curated somatic cancer literature and recurrent somatic observation in cancer resources, a verified TP53 Cancer Hotspots hotspot assignment for codon 194 or for p.Leu194Arg was not established from the reviewed hotspot evidence. Available evidence does not support applying PM1 under the TP53 VCEP rule. Details ▾Hide ▴
Rule
TP53 VCEP PM1 requires a listed hotspot codon or 2-9 / >=10 same-amino-acid somatic occurrences in cancerhotspots.org.
Evidence considered
- Cancer Hotspots review was marked uncertain.
- OncoKB identified variant-specific curated somatic literature.
Still missing
- A verified Cancer Hotspots residue or exact-variant hotspot assignment for p.Leu194Arg was not established.
Sources
BA1 This variant is far below the TP53 BA1 threshold of 0.001. In gnomAD v4.1 the total allele frequency is 6.20e-07, so BA1 is not met. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency >= 0.001.
Evidence considered
- gnomAD v4 total AF 6.195065258817436e-07.
Sources
BS1 This variant is below the TP53 BS1 threshold. In gnomAD v4.1 the total allele frequency is 6.20e-07, and the highest observed subgroup frequency is 3.38e-05 from a single Ashkenazi Jewish allele, which does not meet the BS1 threshold of >=0.0003. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency >= 0.0003 in an eligible ancestry group.
Evidence considered
- gnomAD v4 total AF 6.195065258817436e-07.
- Highest gnomAD v4 subgroup AF is 3.377693710734311e-05.
Sources
BS3 Available functional evidence does not support retained TP53 function. The TP53 VCEP functional worksheet lists p.Leu194Arg as non-functional and loss-of-function across eligible assay categories, which argues against BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires functional evidence showing no loss of function.
Evidence considered
- Functional worksheet row for L194R is pre-assigned PS3
- not BS3.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
BP4 Available computational evidence does not support a benign prediction. In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate rather than BP4; BayesDel is 0.582962, which is well above the benign ranges, and REVEL is 0.933. SpliceAI shows no significant splice effect (max delta score 0.13), but the missense prediction remains damaging overall. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires benign BayesDel thresholds with no predicted splice effect; those conditions are not met.
Evidence considered
- PP3-BP4 worksheet row assigns PP3_moderate.
- BayesDel score 0.582962.
- REVEL score 0.933.
- SpliceAI max delta score 0.13.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
Not assessed · 8 · no assessment recorded
PS1 PS1 requires a different nucleotide change that results in the same amino acid substitution and has a TP53 VCEP pathogenic assertion. Such evidence was not identified in the reviewed sources, so PS1 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires a different nucleotide change encoding the same amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic assertion.
Evidence considered
- ClinVar contains the exact c.581T>G variant with TP53 VCEP review.
Still missing
- No reviewed source documented a different nucleotide change causing p.Leu194Arg with a TP53 VCEP pathogenic assertion.
Sources
PS2 No confirmed de novo observation with the TP53-specific point-based cancer criteria was identified, so PS2 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS2 uses Li-Fraumeni syndrome cancer point thresholds.
Evidence considered
- TP53 PS2 is point-based and requires proband-level clinical data.
Still missing
- No maternity/paternity-confirmed de novo case was identified.
- No proband-specific TP53 PS2 point assignment was available.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 The population data support PM2_Supporting, but no proband-level Li-Fraumeni syndrome point data or affected-case series were identified to score PS4 under the TP53 VCEP framework, so PS4 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS4 uses point-based case observations after PM2_Supporting is satisfied.
Evidence considered
- Variant is rare enough for PM2_Supporting.
- No proband-specific PS4 point assignments were available.
Still missing
- No unrelated proband observations with TP53 PS4 cancer-point totals were identified.
- No case-enrichment dataset for this variant was identified.
Sources
PM5 PM5 requires a different missense change at the same residue with a prior TP53 VCEP pathogenic or likely pathogenic assertion. Such residue-level evidence was not identified in the reviewed sources, so PM5 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PM5 is based on prior TP53 VCEP classifications at the same amino acid residue.
Evidence considered
- ClinVar confirms the exact variant classification but does not provide reviewed residue-level PM5 support in the current materials.
Still missing
- No reviewed source documented another TP53 VCEP-classified pathogenic or likely pathogenic missense variant at codon 194.
Sources
PP1 No segregation data with informative meioses were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP1 uses 3-4, 5-6, or >=7 meioses for Supporting, Moderate, or Strong evidence.
Evidence considered
- TP53 PP1 requires cosegregation across informative meioses.
Still missing
- No family segregation study with 3 or more informative meioses was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 TP53 PP4 is based on low-variant-allele-fraction observations in the appropriate clinical context. No proband-specific variant allele fraction or mosaicism-focused clinical evidence was identified, so PP4 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP4 uses variant allele fraction thresholds in the appropriate clinical setting.
Evidence considered
- TP53 PP4 requires VAF-based clinical observations.
Still missing
- No blood or non-lymphocyte tissue VAF data were identified.
- No qualifying TP53 PP4 observation was identified.
Sources
BS2 No single-source cohort showing unaffected women age 60 years or older carrying this variant was identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS2 uses counts of unaffected females age >=60 years from a single source.
Evidence considered
- TP53 BS2 requires unaffected older female carriers from a single source.
Still missing
- No qualifying unaffected carrier series was identified.
Sources
BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS4 applies to lack of segregation in affected family members with LFS-associated cancers.
Evidence considered
- TP53 BS4 requires lack of segregation in affected family members.
Still missing
- No informative non-segregation study was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM4 as not applicable.
Sources
PM6 N/APM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP2 as not applicable.
Sources
BP1 N/ABP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP1 as not applicable.
Sources
BP2 N/ABP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is intended for synonymous or relevant intronic variants without splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or intronic variants meeting splice-related criteria.
Evidence considered
- Variant consequence is missense p.Leu194Arg.
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.581T>G
- Protein (HGVS p.)
- NP_000537.3:p.(Leu194Arg)
- GRCh38
- chr17:7674950 A>C
- GRCh37
- chr17:7578268 A>C
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 / 1,614,188 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,486 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,188 alleles · 0 hom
| Ashkenazi Jewish1 / 29,606 | 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).
gnomAD v2.1
AF 4e-06 · 1 / 251,486 alleles · 0 hom
| Ashkenazi Jewish1 / 10,080 | 9.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19507e-07; MAF= 0.00006%, 1/1614188 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97636e-06; MAF= 0.00040%, 1/251486 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ModerateIn the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate. BayesDel is 0.582962, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect rather than a splicing mechanism. Details ▾Hide ▴
Rule
TP53 VCEP PP3 Moderate for missense variants with aGVGD C65 and BayesDel >= 0.16.
Evidence considered
- PP3-BP4 worksheet row: c.581T>G | p.Leu194Arg | Class C65 | 0.582962 | PP3_moderate | 0.13.
- REVEL score 0.933.
- SpliceAI max delta score 0.13.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
BP4 Available computational evidence does not support a benign prediction. In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate rather than BP4; BayesDel is 0.582962, which is well above the benign ranges, and REVEL is 0.933. SpliceAI shows no significant splice effect (max delta score 0.13), but the missense prediction remains damaging overall. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires benign BayesDel thresholds with no predicted splice effect; those conditions are not met.
Evidence considered
- PP3-BP4 worksheet row assigns PP3_moderate.
- BayesDel score 0.582962.
- REVEL score 0.933.
- SpliceAI max delta score 0.13.
Sources
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗cspec ↗
BP7 N/ABP7 is intended for synonymous or relevant intronic variants without splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or intronic variants meeting splice-related criteria.
Evidence considered
- Variant consequence is missense p.Leu194Arg.
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 = 0.13). REVEL score = 0.933. BayesDel score = 0.582962.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,188 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/376633/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578268-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674950-A-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.581T…
- OncoKB ↗www.oncokb.org/gene/TP53/L194R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104362396
- 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= 6.19507e-07; MAF= 0.00006%, 1/1614188 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97636e-06; MAF= 0.00040%, 1/251486 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.933. BayesDel score = 0.582962.
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; COSV52679257, n = 156 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.