About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.840A>T, p.(Arg280Ser)
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.(Arg280Ser) is listed as non-functional in the Kato transactivation assay and as loss of function across additional eligible assays, which supports PS3 at strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,613,914 alleles; AF 6.19612e-07; highest non-founder subpopulation AF 8.47432e-07 in non-Finnish Europeans), which is below the TP53 VCEP PM2 threshold of 0.00003 and below the multi-allele ancestry threshold of 0.00004.
PP3Moderate
PP3 · moderate
The TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate to c.840A>T based on aGVGD Class C65 and BayesDel 0.519515. Local computational data are concordant, with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no meaningful splice effect (max delta score 0.01). These findings support 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 / 1,613,914 alleles
gnomAD v4.1: 1 / 1,613,914 alleles. Recorded AF 6.19612e-07. 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: 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 · 4 not met · 9 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.840A>T (p.Arg280Ser) variant has been observed in somatic cancer resources and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as pathogenic.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,613,914 alleles; AF 6.19612e-07), which is below the TP53 PM2 threshold of 0.00003.
In the TP53 VCEP functional worksheet, p.Arg280Ser is non-functional in the Kato assay and shows loss of function across additional eligible assays, supporting PS3.
TP53 VCEP in silico resources assign PP3_Moderate for c.840A>T based on aGVGD Class C65 and BayesDel 0.519515; local computational data are concordant with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no significant splice impact (max delta score 0.01).
No criteria match.
Met · 4
PS3 StrongIn the TP53 VCEP functional worksheet, p.(Arg280Ser) is listed as non-functional in the Kato transactivation assay and as loss of function across additional eligible assays, which supports 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
- Functional worksheet row: R280S | NA | Non-functional | LOF | LOF | LOF | NA | PS3
- TP53 VCEP functional flowchart and worksheet provide the pre-assigned code.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,613,914 alleles; AF 6.19612e-07; highest non-founder subpopulation AF 8.47432e-07 in non-Finnish Europeans), which is below the TP53 VCEP PM2 threshold of 0.00003 and below the multi-allele ancestry threshold of 0.00004. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: AF < 0.00003, and if multiple alleles are present within a genetic ancestry group, frequency in that group must be < 0.00004.
Evidence considered
- gnomAD v2.1 absent.
- gnomAD v4.1 AF 6.196117017387543e-07
- AC 1/AN 1613914.
- Highest observed non-founder subpopulation AF 8.474317732679342e-07 in NFE
- AC 1/AN 1180036.
Sources
PP3 ModerateThe TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate to c.840A>T based on aGVGD Class C65 and BayesDel 0.519515. Local computational data are concordant, with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no meaningful splice effect (max delta score 0.01). These findings support a damaging missense effect rather than a splicing mechanism. Details ▾Hide ▴
Rule
TP53 missense PP3_Moderate: aGVGD Class C65 and BayesDel score at or above 0.16, with no alternative splice explanation from SpliceAI.
Evidence considered
- PP3/BP4 worksheet row: c.840A>T | p.Arg280Ser | Class C65 | 0.519515 | PP3_moderate | 0.01
- Local BayesDel score 0.471463.
- REVEL score 0.878.
- SpliceAI max delta score 0.01.
Sources
Not met · 4 · evaluated, threshold not reached
BA1 The observed population frequency is far below the TP53 VCEP BA1 threshold of 0.001. In gnomAD v4.1, this variant is present only once (AF 6.19612e-07), and it is absent from gnomAD v2.1. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency at or above 0.001 in an eligible non-founder ancestry group.
Evidence considered
- gnomAD v2.1 absent.
- gnomAD v4.1 AF 6.196117017387543e-07
- AC 1/AN 1613914.
Sources
BS1 The observed population frequency does not reach the TP53 VCEP BS1 threshold of 0.0003. In gnomAD v4.1, this variant is present once (AF 6.19612e-07), and no qualifying subpopulation frequency above threshold was identified. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency at or above 0.0003 but below 0.001 in an eligible non-founder ancestry group.
Evidence considered
- gnomAD v4.1 AF 6.196117017387543e-07
- AC 1/AN 1613914.
- Highest observed non-founder subpopulation AF 8.474317732679342e-07 in NFE.
Sources
BS3 Available functional evidence does not support retained TP53 function. In the TP53 VCEP functional worksheet, p.(Arg280Ser) is non-functional in Kato data and shows loss of function across other eligible assays, which argues against BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires functional evidence consistent with retained or partially retained function without evidence of loss of function across eligible assays.
Evidence considered
- Functional worksheet row assigns PS3
- not BS3.
- The variant is listed as non-functional/LOF across eligible assays.
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 interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate rather than BP4, with aGVGD Class C65 and BayesDel 0.519515; local BayesDel is also elevated at 0.471463. Although SpliceAI predicts no meaningful splice effect (max delta score 0.01), the missense prediction data support deleteriousness rather than BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires non-damaging missense prediction with BayesDel below PP3 thresholds and no predicted splice impact.
Evidence considered
- PP3/BP4 worksheet assigns PP3_moderate.
- Worksheet BayesDel 0.519515 and local BayesDel 0.471463.
- SpliceAI max delta score 0.01.
- REVEL 0.878.
Sources
Not assessed · 9 · no assessment recorded
PS1 No independently verified TP53 VCEP-qualified alternate nucleotide change encoding the same amino acid substitution was identified in the reviewed evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires a previously classified same-amino-acid change under the TP53 VCEP framework.
Evidence considered
- The reviewed evidence confirms the exact variant p.(Arg280Ser) in ClinVar but does not provide a verified TP53 VCEP-qualified PS1 comparator.
Still missing
- A same-amino-acid comparator classified as Pathogenic or Likely Pathogenic under TP53 VCEP specifications would be needed.
Sources
PS2 No de novo observations with the phenotype-specific point framework, parental confirmation, or case-level scoring data were identified, so PS2 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PS2 is point based.
Evidence considered
- No scored de novo probands were identified in the reviewed materials.
Still missing
- Case-level de novo data with TP53 VCEP point scoring are needed.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 This variant is very rare in population databases, satisfying the population prerequisite for TP53 PS4 review, but no countable set of germline probands with TP53 VCEP point totals was identified, so PS4 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PS4 is point based and requires qualifying affected proband evidence after PM2_Supporting-level rarity is satisfied.
Evidence considered
- gnomAD v2.1 absent.
- gnomAD v4.1 total AF 6.196117017387543e-07
- 1/1613914 alleles.
Still missing
- Affected proband data with TP53 PS4 point scoring are needed.
Sources
PM1 Codon 280 is not one of the TP53 VCEP codons that automatically qualify for PM1, and the available Cancer Hotspots capture for exact-variant recurrence was inconclusive and flagged for human review, so PM1 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PM1 uses specified codons or exact amino acid change recurrence thresholds in Cancer Hotspots.
Evidence considered
- TP53 automatic PM1 codons are 175
- 245
- 248
- 249
- 273
- and 282.
- Cancer Hotspots extraction for R280S was uncertain and not validated.
Still missing
- A verified exact amino acid change count from Cancer Hotspots showing at least 2 or at least 10 somatic occurrences would be needed for TP53 VCEP PM1.
Sources
PM5 A verified TP53 VCEP-qualified same-residue pathogenic comparator was not established from the reviewed evidence, so PM5 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PM5 uses prior pathogenic or likely pathogenic missense changes at the same residue under the TP53 framework.
Evidence considered
- The PM5 candidate artifact did not provide usable same-residue comparator support for this case.
Still missing
- Expert-panel or TP53 VCEP-qualified pathogenic same-residue missense comparator data are needed.
Sources
cspec ↗pm5_candidates
PP1 No segregation data with meiosis counts in families affected by Li-Fraumeni syndrome-associated cancers were identified, so PP1 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires 3-4, 5-6, or at least 7 meioses depending on strength.
Evidence considered
- No qualifying cosegregation evidence was identified.
Still missing
- Family segregation data with TP53 VCEP point-eligible phenotypes and meiosis counts are needed.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No case-level blood variant allele fraction data or repeat observations meeting the TP53 mosaicism-focused PP4 framework were identified, so PP4 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP PP4 is based on observations of low-level blood variant allele fractions and recurrence thresholds.
Evidence considered
- No qualifying TP53 PP4 observation data were provided.
Still missing
- Observation data with variant allele fraction in blood and the required number of independent observations are needed.
Sources
BS2 No single-source dataset demonstrating unaffected females at age 60 years or older with this variant was identified, so BS2 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is based on unrelated unaffected older female carriers from a single source.
Evidence considered
- No TP53 BS2 carrier-count evidence was identified.
Still missing
- A qualifying single-source unaffected carrier dataset is needed.
Sources
BS4 No non-segregation evidence in relatives affected with Li-Fraumeni syndrome-associated cancers was identified, so BS4 was not applied. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers.
Evidence considered
- No qualifying BS4 family data were identified.
Still missing
- Family-based non-segregation data are needed.
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 TP53-specific PVS1 materials do not support applying a null-variant criterion to p.(Arg280Ser). SpliceAI also predicts no meaningful splice disruption (max delta score 0.01), so available evidence does not support a PVS1 mechanism. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 applies to qualifying null/splice mechanisms, which are not supported for this missense variant.
Evidence considered
- TP53 germline loss of function is an established mechanism in the VCEP framework
- but this specific variant is not a nonsense
- frameshift
- canonical splice
- initiation-loss
- or deletion event.
- SpliceAI max delta score is 0.01.
Sources
PM3 N/APM3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM4 N/APM4 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM6 N/APM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP2 N/ABP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP5 N/ABP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is a synonymous or intronic rule and does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
- The variant causes p.(Arg280Ser)
- a missense substitution.
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.840A>T
- Protein (HGVS p.)
- NP_000537.3:p.(Arg280Ser)
- GRCh38
- chr17:7673780 T>A
- GRCh37
- chr17:7577098 T>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
1 / 1,613,914 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 / 1,613,914 alleles · 0 hom
| European (non-Finnish)1 / 1,180,036 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19612e-07; MAF= 0.00006%, 1/1613914 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-07; MAF= 0.00008%, 1/1180036 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 ModerateThe TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate to c.840A>T based on aGVGD Class C65 and BayesDel 0.519515. Local computational data are concordant, with BayesDel 0.471463 and REVEL 0.878, while SpliceAI predicts no meaningful splice effect (max delta score 0.01). These findings support a damaging missense effect rather than a splicing mechanism. Details ▾Hide ▴
Rule
TP53 missense PP3_Moderate: aGVGD Class C65 and BayesDel score at or above 0.16, with no alternative splice explanation from SpliceAI.
Evidence considered
- PP3/BP4 worksheet row: c.840A>T | p.Arg280Ser | Class C65 | 0.519515 | PP3_moderate | 0.01
- Local BayesDel score 0.471463.
- REVEL score 0.878.
- SpliceAI max delta score 0.01.
Sources
BP4 Available computational evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3_Moderate rather than BP4, with aGVGD Class C65 and BayesDel 0.519515; local BayesDel is also elevated at 0.471463. Although SpliceAI predicts no meaningful splice effect (max delta score 0.01), the missense prediction data support deleteriousness rather than BP4. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires non-damaging missense prediction with BayesDel below PP3 thresholds and no predicted splice impact.
Evidence considered
- PP3/BP4 worksheet assigns PP3_moderate.
- Worksheet BayesDel 0.519515 and local BayesDel 0.471463.
- SpliceAI max delta score 0.01.
- REVEL 0.878.
Sources
BP7 N/ABP7 is a synonymous or intronic rule and does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
- The variant causes p.(Arg280Ser)
- a missense substitution.
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 = 0.01). REVEL score = 0.878. BayesDel score = 0.471463.
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 / 1,613,914 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/988616/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577098-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7673780-T-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.840A…
- OncoKB ↗www.oncokb.org/gene/TP53/R280S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104419588
- 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= 6.19612e-07; MAF= 0.00006%, 1/1613914 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-07; MAF= 0.00008%, 1/1180036 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 988616)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.878. BayesDel score = 0.471463.
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; COSV52801834, n = 28 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.