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LYFE SCIENCES
Project: HERA
NM_000546.5:c.840A>T
p.Arg280Ser  ·  TP53
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Classification rationale
1

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.

oncokb ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:29979965 ↗ PMID:30224644 ↗
4

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).

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.878. BayesDel score = 0.471463.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52801834, n = 28 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR280
Hotspots ↗