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.1 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 0.00003.2 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 PS3.3 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).4
Final classification
Likely Pathogenic
PS3PM2PP3PP5
TP53
c.840A>T
p.Arg280Ser
This variant
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.
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.
Classification rationale
PS3PM2PP3PP5
Likely Pathogenic
TP53 c.840A>T
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗
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.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
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.
Functional worksheet row: R280S | NA | Non-functional | LOF | LOF | LOF | NA | PS3TP53 VCEP functional flowchart and worksheet provide the pre-assigned code.
PM2
supporting
Pathogenic
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.
gnomAD v2.1 absent.gnomAD v4.1 AF 6.196117017387543e-07AC 1/AN 1613914.
PP3
moderate
Pathogenic
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.
PP3/BP4 worksheet row: c.840A>T | p.Arg280Ser | Class C65 | 0.519515 | PP3_moderate | 0.01Local BayesDel score 0.471463.REVEL score 0.878.
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
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.
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.
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.
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.
PM5
A verified TP53 VCEP-qualified same-residue pathogenic comparator was not established from the reviewed evidence, so PM5 was not applied.
PP1
No segregation data with meiosis counts in families affected by Li-Fraumeni syndrome-associated cancers were identified, so PP1 was not applied.
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.
Benign
BA1
The observed population frequency is far below the TP53 VCEP BA1 threshold of 0.001.
BS1
The observed population frequency does not reach the TP53 VCEP BS1 threshold of 0.0003.
BS2
No single-source dataset demonstrating unaffected females at age 60 years or older with this variant was identified, so BS2 was not applied.
BS3
Available functional evidence does not support retained TP53 function.
BS4
No non-segregation evidence in relatives affected with Li-Fraumeni syndrome-associated cancers was identified, so BS4 was not applied.
BP4
Available computational evidence does not support a benign interpretation.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,914
0 hom
0 hom
European (non-Finnish) 1 / 1,180,036 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
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 in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52801834, n = 28 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links