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
TP53
Final classification
Likely Pathogenic
TP53 c.840A>T · p.Arg280Ser
TP53
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 ↗
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:29979965
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:30224644
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links