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NM_000546.6:c.840A>C
p.Arg280Ser · TP53
0%
complete
Final classification
Likely Pathogenic
PS3PM2PP3
TP53
c.840A>C
p.Arg280Ser
missense · exon 8

TP53 encodes the p53 protein, a critical tumor suppressor that acts as a transcription factor to protect cells from damage. When activated by cellular stress such as DNA damage, p53 triggers responses including DNA repair, cell cycle arrest, and programmed cell death (apoptosis) to prevent the propagation of damaged cells. TP53 is the most frequently mutated gene in human cancers, and loss of its function contributes to tumor development, invasion, drug resistance, and genomic instability. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a rare hereditary condition that greatly increases the risk of developing multiple types of cancer at a young age.

This variant

TP53 is a tumor suppressor whose loss of function drives cancer and, when inherited, causes Li-Fraumeni syndrome with high early-life cancer risk. This likely pathogenic Arg280Ser missense change is predicted to impair p53's protective function - consistent with functional assays showing loss of function and its absence from population databases - so it should be treated as conferring Li-Fraumeni syndrome-associated cancer risk.

Transcript
NM_000546.6
HGVS · transcript:coding
NM_000546.6:c.840A>C
GRCh38
chr17:7673780 T>G
GRCh37
chr17:7577098 T>G
Likely Pathogenic: 7 points under the ClinGen TP53 VCEP Version 2.4 framework - PS3 strong (+4), PM2 supporting (+1), PP3 moderate (+2).
Classification rationale
PS3PM2PP3 Likely Pathogenic
TP53 c.840A>C missense · exon 8

PS3 (Strong): functional assays demonstrate loss of function - non-functional on Kato data and loss of function in most other eligible assays. PM2 (Supporting): the variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0. PP3 (Moderate): VCEP pre-computed assignment records Align-GVGD Class C65 and BayesDel 0.47, supporting a pathogenic effect. Likely Pathogenic: 7 points under the TP53 VCEP v2.4 framework (PS3 strong +4, PM2 supporting +1, PP3 moderate +2).

PS3 + PM2 + PP3 → Likely Pathogenic
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_000546.6 · variants mapped to exon structure
TP53 NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 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 · 3
Strength Supporting Moderate Strong Very strong
PS3 strong Pathogenic
Met (Strong): functional assays show loss of function - non-functional on Kato data and loss of function in most other eligible assays.
CHECKLIST ps3_1: Is the variant non-functional on Kato et al. data? — TRUE — The exact R280S row in the TP53 Functional Worksheet records Kato as Non-functional.CHECKLIST ps3_2: Is there loss of function (LOF) by the majority of other eligible assays? — TRUE — The exact R280S row records LOF in the majority of the other eligible assay columns.CHECKLIST ps3_3: Is the variant partially functional on Kato et al. data? — FALSE — The exact R280S Kato result is Non-functional, not partially functional.
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0, below the 0.00003 allele-frequency threshold.
CHECKLIST item pm2_1: Is the variant absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium? — NA — Those three legacy resources are not separately reported in the case bundle, although the exact variant is absent from the supplied gnomAD control datasets.CHECKLIST item pm2_2: For an indel, was the poor calling of population data by next generation sequencing considered? — FALSE — This variant is a single-nucleotide substitution, not an indel.CHECKLIST item pm2_3: Is PM2 applied at supporting level? — TRUE — The TP53 VCEP explicitly requires PM2 to be applied at Supporting level.
PP3 moderate Pathogenic
Met (Moderate): VCEP pre-computed assignment for Arg280Ser - Align-GVGD Class C65 and BayesDel 0.47 - supports a pathogenic effect.
TP53 VCEP Supplementary Table S2 directly assigns PP3_moderate to c.840A>C / p.Arg280Ser, with Align-GVGD Class C65 and BayesDel 0.471465.SpliceAI maximum delta score is 0.004 (reported as 0.00), below the VCEP threshold for a predicted splice effect; this supports interpretation through the missense computational pathway only.
Assessed · not applied · 5 not met · 10 not assessed
Pathogenic
PVS1 Not met: a missense substitution with no predicted splice impact (max SpliceAI delta 0.004), so no loss-of-function null mechanism applies.
PS1 Not assessed: the only available ClinVar submissions are non-expert-panel, so no qualifying pathogenic same-amino-acid comparator exists.
PS2 Not assessed: no proband parental-testing, mosaicism, or family-history data were available to establish a de novo origin.
PS4 Not assessed: no case-control prevalence or verified Li-Fraumeni proband data were available for point scoring.
PM1 Not assessed: codon 280 falls outside the VCEP hotspot codons (175, 245, 248, 249, 273, 282), and no Arg280Ser occurrence count was available.
PM5 Not assessed: insufficient evidence was available - no qualifying same-residue pathogenic comparator variant could be confirmed.
PM6 Not assessed: no documentation that the variant is assumed de novo, or the proband phenotype needed to score it, was available.
PP1 Not assessed: no family carrier-testing, affected-relative, or meiosis data were available for cosegregation scoring.
PP4 Not assessed: no blood or tumor variant-allele-fraction or independent observation-count data were available.
Benign
BA1 Not met: absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, so no population frequency reached the 0.001 BA1 threshold.
BS1 Not met: absent from gnomAD v4.1, v2.1, and gnomAD-Canada v1.0, so no frequency fell in the required 0.0003-0.001 range.
BS2 Not assessed: no cohort data on unrelated female carriers who reached age 60 without cancer were available.
BS3 Not met: functional assays show loss of function, failing the benign functional pathway BS3 requires.
BS4 Not assessed: no affected-relative variant results or phenotype data were available to test lack of segregation.
BP4 Not met: the VCEP worksheet assigns pathogenic-direction PP3_moderate to this variant, not benign-direction BP4.
N/A · 10 PM3 · PM4 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory). (ClinVarID = 634747)
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.878. BayesDel score = 0.471465.
Functional / OncoKB screenshot
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52782181, n = 13 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. 4 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
12826609 ↗ Understanding the function-structure and function-mutation relationships of p53
29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 4 PMIDs not cited in assessment
10761706 ↗ Mutations in zinc-binding domains of p53 as a prognostic marker of esophageal-ca ONCOKB
27328919 ↗ TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Ge ONCOKB
20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genom CLINVAR
20301471 ↗ Wilms Tumor Predisposition. CLINVAR