About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.1009C>T, p.(Arg337Cys)
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.Arg337Cys is assigned PS3. The compiled assay results list the variant as non-functional in Kato, loss-of-function in Giacomelli, and monomer in Kawaguchi, supporting a damaging effect on p53 function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and has 0/1,613,822 alleles in gnomAD v4.1, which is below the TP53 PM2 threshold of less than 0.00003 overall and below the single-population threshold of less than 0.00004.
PP3Supporting
PP3 · supporting
For the TP53 missense-specific in silico framework, the VCEP worksheet assigns PP3 to c.1009C>T (p.Arg337Cys). BayesDel is 0.316468, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.715, and SpliceAI shows no predicted 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
0 / 1,613,822 alleles
gnomAD v4.1: 0 / 1,613,822 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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: 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 · 5 not met · 8 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.1009C>T (p.Arg337Cys) variant has been observed in somatic cancer resources and is reported in ClinVar with a Pathogenic expert-panel assertion.
This variant is absent from gnomAD v2.1 and is not observed in gnomAD v4.1 (0/1613822 alleles), which supports rarity under the TP53 PM2_Supporting threshold.
In the TP53 VCEP functional framework, published assay evidence compiled in the expert-panel worksheet shows p.Arg337Cys is non-functional or loss-of-function, with a PS3 assignment supporting a damaging effect on p53 activity.
For in silico evaluation, the TP53 VCEP bioinformatic worksheet assigns PP3 to this missense change; BayesDel is 0.316468, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00).
No criteria match.
Met · 4
PS3 StrongIn the TP53 VCEP functional worksheet, p.Arg337Cys is assigned PS3. The compiled assay results list the variant as non-functional in Kato, loss-of-function in Giacomelli, and monomer in Kawaguchi, supporting a damaging effect on p53 function. Details ▾Hide ▴
Rule
TP53 VCEP PS3 is supported by qualifying non-functional/loss-of-function assay results in the approved functional framework.
Evidence considered
- Functional worksheet row: R337C | NA | Non-functional | NA | LOF | NA | Monomer | PS3.
- TP53 VCEP functional flowchart designates pre-assigned functional codes from eligible assays.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and has 0/1,613,822 alleles in gnomAD v4.1, which is below the TP53 PM2 threshold of less than 0.00003 overall and below the single-population threshold of less than 0.00004. Details ▾Hide ▴
Rule
TP53 VCEP PM2 is applied at supporting strength for AF <0.00003 overall and <0.00004 in any qualifying ancestry group.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: total AF 0.0
- AC 0/1
- 613
- 822
- highest observed subpopulation AF 0.0
- AC 0/74
- 914 in African/African American.
Sources
PP3 SupportingFor the TP53 missense-specific in silico framework, the VCEP worksheet assigns PP3 to c.1009C>T (p.Arg337Cys). BayesDel is 0.316468, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 VCEP uses the approved PP3/BP4 worksheet with BayesDel and Align-GVGD for missense variants, with splicing checked separately by SpliceAI.
Evidence considered
- PP3-BP4 worksheet row: c.1009C>T | p.Arg337Cys | Class C45 | 0.316468 | PP3 | 0.01.
- REVEL score 0.715.
- SpliceAI max delta score 0.00.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗
Not met · 5 · evaluated, threshold not reached
PM1 p.Arg337Cys is not one of the TP53 codons with automatic PM1 application, and the available hotspot review did not verify the Cancer Hotspots evidence needed to use the alternative somatic-occurrence PM1 rule. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to codons 175, 245, 248, 249, 273, and 282, or to variants with qualifying Cancer Hotspots same-amino-acid counts.
Evidence considered
- TP53 default PM1 codons are limited in the VCEP specification.
- Cancer Hotspots review for this residue was marked uncertain and needed human review.
Still missing
- Cancer Hotspots same-amino-acid occurrence threshold was not verified from a reviewable source.
Sources
BA1 This variant does not meet BA1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BA1 threshold of at least 0.001. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires a qualifying subpopulation filtering allele frequency of at least 0.001.
Evidence considered
- gnomAD v4.1 total AF 0.0
- AC 0/1
- 613
- 822.
Sources
BS1 This variant does not meet BS1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BS1 threshold of at least 0.0003. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires a qualifying subpopulation filtering allele frequency of at least 0.0003 and less than 0.001.
Evidence considered
- gnomAD v4.1 total AF 0.0
- AC 0/1
- 613
- 822.
Sources
BS3 Available TP53 functional evidence does not support retained or partially retained p53 function. Instead, the VCEP functional worksheet assigns PS3 based on non-functional and loss-of-function results, so BS3 is not met. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires retained or partially retained function without evidence for loss of function in the approved assay framework.
Evidence considered
- Functional worksheet assigns PS3
- not BS3
- for R337C.
Sources
BP4 BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3, not BP4, to p.Arg337Cys. BayesDel is 0.316468, which is above the pathogenic threshold of 0.16, although SpliceAI predicts no splice effect. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires BayesDel below the benign thresholds with no predicted splice effect.
Evidence considered
- PP3-BP4 worksheet row assigns PP3 for c.1009C>T.
- BayesDel score 0.316468.
- SpliceAI max delta score 0.00.
Sources
Not assessed · 8 · no assessment recorded
PS1 No verified evidence was identified showing that a different nucleotide change produces the same amino acid substitution and has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires a same-amino-acid comparator previously classified as Pathogenic or Likely Pathogenic under the TP53 specifications.
Evidence considered
- ClinVar confirms this exact variant has an expert-panel assertion
- but no qualifying alternate nucleotide producing the same amino acid change was verified here.
Still missing
- Same-amino-acid comparator review was not verified from an expert-panel source.
Sources
PS2 No confirmed de novo observation with sufficient clinical point scoring was identified for this variant, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
TP53 VCEP PS2 requires qualifying de novo observations scored by the TP53 point table.
Evidence considered
- TP53 VCEP PS2 uses a point-based de novo framework
- but no qualifying proband-level data were verified.
Still missing
- Case-level de novo evidence with parental confirmation was not identified.
- No PS2 point total could be calculated.
Sources
PS4 This variant is rare enough to satisfy the TP53 rarity gate for PS4 evaluation, but no verified proband-based Li-Fraumeni syndrome point total was identified, so PS4 cannot be applied from the current evidence. Details ▾Hide ▴
Rule
TP53 VCEP PS4 requires PM2_Supporting first and then a qualifying point total from affected probands.
Evidence considered
- Variant is absent from gnomAD v2.1 and 0/1
- 613
- 822 alleles in gnomAD v4.1
- satisfying the population gate used before TP53 PS4 review.
- No verified PS4 point total was available.
Still missing
- No counted qualifying probands with TP53 VCEP PS4 cancer-point assignments were verified.
- No case-enrichment or case-series point total was established.
Sources
PM5 No verified same-residue pathogenic or likely pathogenic comparator variant classified under the TP53 VCEP framework was confirmed for codon 337, so PM5 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PM5 requires a different missense variant at the same residue previously classified as Pathogenic or qualifying Likely Pathogenic under the TP53 specifications.
Evidence considered
- PM5 candidates artifact did not provide a usable verified comparator for adjudication.
Still missing
- Same-residue expert-panel comparator review remains incomplete.
Sources
cspec ↗pm5_candidates
PP1 No segregation data were identified that established cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires cosegregation in informative meioses scored by the TP53 framework.
Evidence considered
- TP53 VCEP PP1 requires 3 or more informative meioses for supporting evidence
- and no qualifying segregation dataset was verified.
Still missing
- No verified pedigree with informative meiosis count was identified.
Sources
PP4 No qualifying low-variant-allele-fraction blood observation or other TP53-specific PP4 data were identified, so PP4 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP PP4 depends on specific low-VAF observations rather than the generic phenotype-only formulation.
Evidence considered
- TP53 VCEP repurposes PP4 for low-VAF observations
- and no such case-level evidence was available.
Still missing
- No VAF-based constitutional mosaicism evidence was identified.
- No qualifying observation count for the TP53 PP4 framework was verified.
Sources
BS2 No source identified 2 or more unrelated women aged at least 60 years without cancer carrying this variant from a single dataset, so BS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is point-based on unaffected older female carriers from one source.
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from a single source.
Still missing
- No qualifying unaffected-carrier dataset was identified.
Sources
BS4 No family data were identified showing lack of segregation of this variant with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be applied. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires demonstrated lack of segregation with LFS-associated cancers.
Evidence considered
- TP53 VCEP BS4 requires lack of segregation in affected family members
- and no such dataset was available.
Still missing
- No verified non-segregation pedigree was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, p.Arg337Cys, with no predicted splice effect (SpliceAI max delta score 0.00), so it does not meet the TP53 null-variant framework for PVS1. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 applies to eligible null or qualifying splice variants, not to a missense variant without predicted splice impact.
Evidence considered
- TP53-specific PVS1 framework is eligible at the gene level
- but this variant is not a nonsense
- frameshift
- canonical +/-1
- 2 splice
- or other null allele.
- SpliceAI shows no predicted splice disruption.
Sources
PM3 N/APM3 is not used in the TP53 VCEP framework for this condition context. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not used in the TP53 VCEP framework for this variant type and disease context. Details ▾Hide ▴
Rule
Not applicable in 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 in 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 in 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 in 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 in 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 in 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 in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is a synonymous or intronic splicing-related code and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants, not to missense variants.
Evidence considered
- Variant consequence is missense
- p.Arg337Cys.
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.1009C>T
- Protein (HGVS p.)
- NP_000537.3:p.(Arg337Cys)
- GRCh38
- chr17:7670700 G>A
- GRCh37
- chr17:7574018 G>A
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
0 / 1,613,822 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,613,822 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613822 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74914 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingFor the TP53 missense-specific in silico framework, the VCEP worksheet assigns PP3 to c.1009C>T (p.Arg337Cys). BayesDel is 0.316468, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00). Details ▾Hide ▴
Rule
TP53 VCEP uses the approved PP3/BP4 worksheet with BayesDel and Align-GVGD for missense variants, with splicing checked separately by SpliceAI.
Evidence considered
- PP3-BP4 worksheet row: c.1009C>T | p.Arg337Cys | Class C45 | 0.316468 | PP3 | 0.01.
- REVEL score 0.715.
- SpliceAI max delta score 0.00.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗
BP4 BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3, not BP4, to p.Arg337Cys. BayesDel is 0.316468, which is above the pathogenic threshold of 0.16, although SpliceAI predicts no splice effect. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires BayesDel below the benign thresholds with no predicted splice effect.
Evidence considered
- PP3-BP4 worksheet row assigns PP3 for c.1009C>T.
- BayesDel score 0.316468.
- SpliceAI max delta score 0.00.
Sources
BP7 N/ABP7 is a synonymous or intronic splicing-related code and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants, not to missense variants.
Evidence considered
- Variant consequence is missense
- p.Arg337Cys.
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 = 0.715. BayesDel score = 0.316468.
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
0 / 1,613,822 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/142536/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7574018-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7670700-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.1009…
- OncoKB ↗www.oncokb.org/gene/TP53/R337C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104357057
- 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= 0; MAF= 0.00000%, 0/1613822 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74914 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (6 clinical laboratories) and as Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142536)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.715. BayesDel score = 0.316468.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV52669243, n = 168 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.