About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.1010G>T, p.(Arg337Leu)
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: 3
Benign evidence criteria: 1
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
In the TP53 VCEP functional worksheet, p.Arg337Leu is summarized as non-functional with loss-of-function findings across eligible assays and monomerization, which supports a damaging effect on TP53 protein function. This meets TP53 PS3 at strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003 (0.003%) in a large sequenced population.
PP5Supporting
PP5 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The TP53 VCEP bioinformatic worksheet assigns BP4 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the no-splicing-impact threshold of 0.2. These findings support BP4.
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) + PP5 supporting (+1) + BP4 supporting (-1) = 5 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.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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>T (p.Arg337Leu; p.R337L) variant has been observed in somatic cancers in COSMIC (COSV52665150, n=69) and has been reported in ClinVar, including a ClinGen TP53 expert panel classification of Likely Pathogenic.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the TP53 PM2_Supporting threshold of less than 0.00003.
In TP53 functional data summarized by the TP53 VCEP, p.Arg337Leu was non-functional with loss-of-function findings and monomerization, supporting a damaging effect on protein function and meeting PS3.
In the TP53-specific computational framework, SpliceAI predicts no splice effect (max delta score 0.00) and the TP53 VCEP bioinformatic worksheet assigns BP4 with a BayesDel score of 0.0670081; REVEL was 0.765, but the TP53 precomputed PP3/BP4 assignment supports BP4 rather than PP3 for this variant.
No criteria match.
Met · 4
PS3 StrongIn the TP53 VCEP functional worksheet, p.Arg337Leu is summarized as non-functional with loss-of-function findings across eligible assays and monomerization, which supports a damaging effect on TP53 protein function. This meets TP53 PS3 at strong strength. Details ▾Hide ▴
Rule
TP53 VCEP PS3: non-functional on Kato data and loss of function by the majority of other eligible assays; preassigned worksheet code = PS3.
Evidence considered
- Functional worksheet row: R337L | NA | Non-functional | NA | LOF | NA | Monomer | PS3
- TP53 VCEP flowchart maps non-functional/LOF assay profiles to PS3
Sources
cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:16007150 ↗PMID:30224644 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of less than 0.00003 (0.003%) in a large sequenced population. Details ▾Hide ▴
Rule
TP53 VCEP PM2 is used at supporting strength for allele frequency <0.00003.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP5 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
BP4 SupportingThe TP53 VCEP bioinformatic worksheet assigns BP4 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the no-splicing-impact threshold of 0.2. These findings support BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4 Supporting for missense variants: BayesDel <0.16 and >-0.008 with no predicted splicing effect; preassigned worksheet code = BP4.
Evidence considered
- PP3-BP4 worksheet row assigns BP4
- BayesDel score 0.0670081
- SpliceAI max delta 0.00
- REVEL score 0.765
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗revelvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Not met · 5 · evaluated, threshold not reached
PM1 This missense variant is not in one of the TP53 codons pre-specified for PM1, and the available hotspot review did not verify that this exact amino acid change is listed in Cancer Hotspots with the somatic recurrence required for TP53 PM1 application. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to specified hotspot codons or exact changes seen in Cancer Hotspots at defined recurrence thresholds.
Evidence considered
- TP53 codon 337 is not among codons 175
- 245
- 248
- 249
- 273
- or 282
- Hotspot assessment remained uncertain
- COSMIC reports 69 somatic occurrences
- but TP53 PM1 is tied to Cancer Hotspots-based rules
Still missing
- Cancer Hotspots review was uncertain for this residue/change.
Sources
PP3 The TP53 VCEP bioinformatic worksheet assigns BP4 rather than PP3 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of at least 0.16, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.765, but the TP53-specific precomputed PP3/BP4 assignment does not support PP3 for this variant. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying in silico evidence; preassigned worksheet code for this variant is not PP3.
Evidence considered
- PP3-BP4 worksheet row: c.1010G>T | p.Arg337Leu | Class C35 | 0.0670081 | BP4
- BayesDel score 0.0670081
- SpliceAI max delta 0.00
- REVEL score 0.765
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗revelvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the TP53 BA1 threshold of at least 0.001 (0.1%) in a qualifying population. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency >=0.001.
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 in a qualifying population. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency >=0.0003 and <0.001.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS3 Available TP53 functional evidence does not show retained function. Instead, the TP53 VCEP functional worksheet summarizes p.Arg337Leu as non-functional with loss-of-function findings, which argues against BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires retained or partially retained function without evidence of loss of function; this condition is not met.
Evidence considered
- Functional worksheet assigns PS3
- not BS3
- for R337L
Sources
cspec ↗vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:16007150 ↗PMID:30224644 ↗
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified by the TP53 VCEP at a qualifying pathogenic or likely pathogenic level. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires a previously classified pathogenic or likely pathogenic variant causing the same amino acid change.
Evidence considered
- ClinVar entry for this exact variant was reviewed
Still missing
- A same-amino-acid alternate nucleotide comparator was not documented.
Sources
PS2 No confirmed de novo observations with the point-based TP53 evidence required for PS2 were identified. Details ▾Hide ▴
Rule
TP53 VCEP PS2 requires 1 to >=8 points from confirmed or assumed de novo observations.
Evidence considered
- TP53 PS2 requires point-based de novo evidence
Still missing
- No parental testing or confirmed de novo report was identified.
- No PS2 point total could be calculated.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 Although this variant is rare in population databases, no case-level TP53 point total from affected individuals was identified to support PS4 under the Li-Fraumeni syndrome scoring framework. Details ▾Hide ▴
Rule
TP53 VCEP PS4 requires 1 to >=8 phenotype-based points in affected probands, after PM2_Supporting is satisfied.
Evidence considered
- PS4 point thresholds are defined in the TP53 VCEP framework
- Variant is absent from gnomAD but affected-case point data were not available
Still missing
- No proband-level cancer history points were identified.
- No PS4 score could be calculated from the available evidence.
Sources
PM5 No qualifying same-residue pathogenic or likely pathogenic comparator variant was confirmed from the available reviewed materials, so PM5 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PM5 requires a different missense change at the same residue previously determined to be pathogenic or likely pathogenic under the TP53 framework.
Evidence considered
- PM5 candidate artifact did not provide a usable comparator determination
- ClinVar review focused on the exact variant
Still missing
- No validated same-residue TP53 VCEP comparator was documented for codon 337 in the reviewed materials.
Sources
PP1 No segregation data were identified to show cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires cosegregation across 3-4, 5-6, or >=7 meioses depending on strength.
Evidence considered
- TP53 PP1 requires 3 to >=7 informative meioses
Still missing
- No pedigree or meiosis count was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction or mosaicism-related clinical observations were identified to support TP53 PP4. Details ▾Hide ▴
Rule
TP53 VCEP PP4 requires variant observations at defined VAF ranges.
Evidence considered
- TP53 PP4 is based on qualifying low-VAF observations
Still missing
- No VAF-based observation data were identified.
Sources
BS2 No evidence was identified showing this variant in the number of unrelated females age 60 years or older without cancer required for TP53 BS2. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is based on unaffected older female carriers from one source.
Evidence considered
- TP53 BS2 requires 2-3
- 4-7
- or >=8 older unaffected female carriers from a single source
Still missing
- No qualifying unaffected-carrier series from a single source was identified.
Sources
BS4 No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires non-segregation in affected family members.
Evidence considered
- TP53 BS4 requires lack of segregation in affected relatives
Still missing
- No informative non-segregation pedigree was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution, not a nonsense, frameshift, canonical splice, or other null variant. Available evidence does not support a loss-of-function null mechanism for PVS1 application under the TP53-specific framework. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 flowchart for null variants; this missense variant does not enter the PVS1 pathway.
Evidence considered
- NM_000546.6:c.1010G>T encodes p.(Arg337Leu)
- PVS1 scaffold states the variant does not fall into default null-variant buckets
- TP53 VCEP provides PVS1 guidance only for null/splice classes
Sources
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, and this variant is not a protein length-changing in-frame indel or stop-loss event. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM4 as not applicable
- Variant is missense
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 certain intronic variants, whereas this is a missense substitution. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to silent or qualifying intronic variants, not to missense variants.
Evidence considered
- Variant is missense p.(Arg337Leu)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.1010G>T
- Protein (HGVS p.)
- NP_000537.3:p.(Arg337Leu)
- GRCh38
- chr17:7670699 C>A
- GRCh37
- chr17:7574017 C>A
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.
TP53NM_000546.6
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
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
BP4 SupportingThe TP53 VCEP bioinformatic worksheet assigns BP4 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the no-splicing-impact threshold of 0.2. These findings support BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4 Supporting for missense variants: BayesDel <0.16 and >-0.008 with no predicted splicing effect; preassigned worksheet code = BP4.
Evidence considered
- PP3-BP4 worksheet row assigns BP4
- BayesDel score 0.0670081
- SpliceAI max delta 0.00
- REVEL score 0.765
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗revelvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP3 The TP53 VCEP bioinformatic worksheet assigns BP4 rather than PP3 for this variant. BayesDel is 0.0670081, which is below the TP53 PP3 threshold of at least 0.16, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.765, but the TP53-specific precomputed PP3/BP4 assignment does not support PP3 for this variant. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying in silico evidence; preassigned worksheet code for this variant is not PP3.
Evidence considered
- PP3-BP4 worksheet row: c.1010G>T | p.Arg337Leu | Class C35 | 0.0670081 | BP4
- BayesDel score 0.0670081
- SpliceAI max delta 0.00
- REVEL score 0.765
Sources
cspec ↗vcep_pp3_bp4_codesbayesdelspliceai ↗revelvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP7 N/ABP7 is intended for synonymous or certain intronic variants, whereas this is a missense substitution. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to silent or qualifying intronic variants, not to missense variants.
Evidence considered
- Variant is missense p.(Arg337Leu)
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 = 0.765. BayesDel score = 0.0670081.
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 ↗
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/142828/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7574017-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7670699-C-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.1010…
- OncoKB ↗www.oncokb.org/gene/TP53/R337L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104356595
- 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 (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142828)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.765. BayesDel score = 0.0670081.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52665150, n = 69 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.