About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.1010G>C, p.(Arg337Pro)
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.Arg337Pro is listed as non-functional in the Kato transactivation dataset and loss-of-function in the Giacomelli assay framework, with a preliminary TP53 VCEP assignment of PS3, supporting a damaging effect on protein function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall allele frequency and supports PM2 at the supporting level.
PP3Supporting
PP3 · supporting
The TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C based on Align-GVGD class C25 and BayesDel score 0.407328. SpliceAI predicts no splice effect with a maximum delta score of 0.00, and REVEL is high at 0.792, which is consistent with a damaging missense prediction.
PP5Supporting
PP5 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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: 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 · 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.1010G>C (p.Arg337Pro) variant has been observed in somatic cancers in COSMIC (6 occurrences) and has been reported in ClinVar as Likely Pathogenic with expert-panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold.
In the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato dataset and loss-of-function in the Giacomelli framework, supporting a damaging effect on TP53 protein function and PS3.
Computational evidence is also consistent with a damaging missense effect: the TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C, BayesDel is 0.407328, REVEL is 0.792, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 4
PS3 StrongIn the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato transactivation dataset and loss-of-function in the Giacomelli assay framework, with a preliminary TP53 VCEP assignment of PS3, supporting a damaging effect on protein function. Details ▾Hide ▴
Rule
TP53 VCEP PS3: non-functional on Kato and loss of function by the majority of other eligible assays.
Evidence considered
- Functional worksheet row: R337P / Kato non-functional / Giacomelli LOF / preliminary code PS3.
- TP53 VCEP functional flowchart identifies this worksheet as the primary code-assignment source.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall allele frequency and supports PM2 at the supporting level. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: allele frequency less than 0.00003 in large population datasets.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- TP53 VCEP specifies PM2 only at supporting strength.
Sources
PP3 SupportingThe TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C based on Align-GVGD class C25 and BayesDel score 0.407328. SpliceAI predicts no splice effect with a maximum delta score of 0.00, and REVEL is high at 0.792, which is consistent with a damaging missense prediction. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants is based on Align-GVGD and BayesDel, with splicing impact checked by SpliceAI.
Evidence considered
- PP3-BP4 worksheet row: c.1010G>C / p.Arg337Pro / Class C25 / BayesDel 0.407328 / PP3 / SpliceAI 0.
- REVEL score 0.792.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 p.Arg337Pro is not in the TP53 codons specified for PM1_Moderate, and the reviewed evidence did not establish exact Cancer Hotspots support required to apply PM1_Supporting for this amino acid change. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to specified hotspot codons or exact Cancer Hotspots counts.
Evidence considered
- TP53 PM1_Moderate codons are limited in the VCEP specification.
- Hotspot review for R337P was marked uncertain.
Still missing
- Cancer Hotspots residue-level evidence was unresolved in the reviewed materials.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BA1 threshold of at least 0.001 filtering allele frequency in a qualifying ancestry group. Details ▾Hide ▴
Rule
TP53 BA1 requires filtering allele frequency at or above 0.001 in a qualifying population.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 threshold of at least 0.0003 filtering allele frequency in a qualifying ancestry group. Details ▾Hide ▴
Rule
TP53 BS1 requires filtering allele frequency at or above 0.0003 in a qualifying population.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS3 Available functional evidence does not support retained or partially retained TP53 function. Instead, the TP53 VCEP functional worksheet lists p.Arg337Pro as non-functional in Kato and loss-of-function in Giacomelli, which argues against BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires functional or partially functional assay results without evidence of loss of function.
Evidence considered
- Functional worksheet row supports PS3 rather than BS3.
Sources
BP4 Available computational evidence does not support BP4. The TP53 VCEP PP3/BP4 worksheet assigns PP3 rather than BP4 to c.1010G>C, with BayesDel 0.407328, Align-GVGD class C25, and SpliceAI max delta 0.00. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires BayesDel and splicing features consistent with a benign computational prediction.
Evidence considered
- PP3-BP4 worksheet row assigns PP3
- not BP4.
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that a different nucleotide change causing the same p.Arg337Pro amino acid substitution has already been classified by the TP53 VCEP at the strength required for PS1. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously classified pathogenic or likely pathogenic variant under TP53 VCEP specifications.
Evidence considered
- ClinVar confirms the exact variant but does not establish PS1 criteria from an alternate nucleotide change in the reviewed material.
Still missing
- A residue-specific search for alternate nucleotide changes causing p.Arg337Pro was not available in the reviewed sources.
Sources
PS2 No confirmed de novo occurrence with the phenotype-specific TP53 point framework was identified, so PS2 cannot be applied from the currently reviewed evidence. Details ▾Hide ▴
Rule
PS2 requires de novo evidence scored under the TP53 VCEP point table.
Evidence considered
- TP53 VCEP uses a point-based PS2 framework.
- No usable de novo case-level evidence was retrieved for this variant.
Still missing
- No maternity/paternity-confirmed de novo report was identified.
- No proband-level TP53 point assignment was available.
Sources
PS4 Although this variant has been reported in ClinVar and in somatic cancers, no proband-level Li-Fraumeni syndrome point total was identified from the reviewed evidence, so PS4 cannot be assigned. Details ▾Hide ▴
Rule
PS4 requires TP53 VCEP point-based case enrichment evidence.
Evidence considered
- ClinVar expert-panel assertion exists.
- COSMIC records 6 somatic observations.
- TP53 VCEP requires proband-based PS4 point scoring.
Still missing
- No TP53 VCEP PS4 point calculation from germline probands was available.
- No case series with extractable TP53 PS4 point totals was identified.
Sources
PM5 No reviewed source established that one or more different missense variants at codon 337 had already been classified by the TP53 VCEP at the strengths required for PM5. Details ▾Hide ▴
Rule
PM5 requires previously classified pathogenic or likely pathogenic missense variants at the same residue under TP53 VCEP rules.
Evidence considered
- The exact variant is present in ClinVar
- but codon-level TP53 VCEP precedent for other substitutions was not extracted.
Still missing
- A residue-specific TP53 VCEP precedent search for other pathogenic or likely pathogenic codon 337 substitutions was not available in the reviewed sources.
Sources
PP1 No segregation data were identified showing cosegregation of this variant with TP53-associated cancers across the meiosis counts required for PP1. Details ▾Hide ▴
Rule
PP1 requires cosegregation across 3 or more informative meioses under TP53 VCEP thresholds.
Evidence considered
- TP53 VCEP requires meiosis-based segregation counts for PP1.
- No qualifying family data were retrieved.
Still missing
- No pedigree-level segregation data were identified.
- No TP53 VCEP meiosis count could be assigned.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No validated low variant-allele-fraction observation in blood or qualifying mosaicism-style evidence was identified, so PP4 cannot be applied from the reviewed evidence. Details ▾Hide ▴
Rule
PP4 requires qualifying low-VAF observations under TP53 VCEP rules.
Evidence considered
- TP53 VCEP PP4 is based on low-VAF observation criteria.
Still missing
- No qualifying blood VAF observations were identified.
Sources
BS2 No single-source dataset was identified showing the number of unrelated females aged 60 years or older without cancer required to apply BS2. Details ▾Hide ▴
Rule
BS2 requires 2 or more unrelated older unaffected female carriers from a single source, depending on strength.
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from one source.
Still missing
- No qualifying unaffected-carrier count from a single source was identified.
Sources
BS4 No family data were identified showing lack of segregation of this variant with TP53-associated cancers, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BS4 requires documented lack of segregation with TP53-associated cancers.
Evidence considered
- TP53 VCEP BS4 requires lack of segregation in affected relatives.
Still missing
- No non-segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and available evidence does not indicate a nonsense, frameshift, canonical +/-1 or 2 splice, or other TP53 null-variant mechanism required for PVS1 application. Details ▾Hide ▴
Rule
TP53 VCEP/ClinGen SVI PVS1 rules apply to null variants, not straightforward missense substitutions.
Evidence considered
- TP53 VCEP PVS1 guidance applies to null-variant categories.
- The generic PVS1 scaffold states this variant is outside default null-variant buckets.
Sources
PM3 N/APM3 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not applicable because this is not a protein length-changing variant and TP53 VCEP does not use PM4 for this context. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications for this variant type.
Evidence considered
- TP53 VCEP marks PM4 as not applicable.
Sources
PM6 N/APM6 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks PM6 as not applicable.
Sources
PP2 N/APP2 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks PP2 as not applicable.
Sources
BP1 N/ABP1 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks BP1 as not applicable.
Sources
BP2 N/ABP2 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not applicable because this is not an in-frame indel in a repetitive region and TP53 VCEP does not use BP3 here. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications for this variant type.
Evidence considered
- TP53 VCEP marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not applicable for TP53 in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in TP53 VCEP specifications.
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 in TP53 VCEP specifications.
Evidence considered
- TP53 VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or qualifying intronic variants with no splice impact.
Evidence considered
- TP53 BP7 guidance is for synonymous or qualifying intronic variants.
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.1010G>C
- Protein (HGVS p.)
- NP_000537.3:p.(Arg337Pro)
- GRCh38
- chr17:7670699 C>G
- GRCh37
- chr17:7574017 C>G
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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThe TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C based on Align-GVGD class C25 and BayesDel score 0.407328. SpliceAI predicts no splice effect with a maximum delta score of 0.00, and REVEL is high at 0.792, which is consistent with a damaging missense prediction. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants is based on Align-GVGD and BayesDel, with splicing impact checked by SpliceAI.
Evidence considered
- PP3-BP4 worksheet row: c.1010G>C / p.Arg337Pro / Class C25 / BayesDel 0.407328 / PP3 / SpliceAI 0.
- REVEL score 0.792.
Sources
BP4 Available computational evidence does not support BP4. The TP53 VCEP PP3/BP4 worksheet assigns PP3 rather than BP4 to c.1010G>C, with BayesDel 0.407328, Align-GVGD class C25, and SpliceAI max delta 0.00. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires BayesDel and splicing features consistent with a benign computational prediction.
Evidence considered
- PP3-BP4 worksheet row assigns PP3
- not BP4.
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to synonymous or qualifying intronic variants with no splice impact.
Evidence considered
- TP53 BP7 guidance is for synonymous or qualifying intronic variants.
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 = 0.792. BayesDel score = 0.407328.
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
Captured gnomAD v4.1 source record
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/177879/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7574017-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7670699-C-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.1010…
- OncoKB ↗www.oncokb.org/gene/TP53/R337P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104405880
- 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.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (6 clinical laboratories) and as Likely 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 = 0.00). REVEL score = 0.792. BayesDel score = 0.407328.
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; COSV52828545, n = 6 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.