The TP53 c.845G>A (p.Arg282Gln) variant has been reported in ClinVar with conflicting germline classifications and is also described in somatic cancer literature at a recurrent TP53 hotspot residue.1 This variant is rare in population databases, with an allele frequency of 5.58e-06 in gnomAD v4.1 and 3.98e-06 in gnomAD v2.1, which supports PM2 at Supporting strength under the TP53 VCEP thresholds.2 Available functional evidence is mixed and does not meet TP53 VCEP criteria for either damaging or benign functional evidence; the TP53 functional worksheet assigns p.Arg282Gln as 'No evidence' for PS3/BS3.3 Computational evidence supports a deleterious effect because the TP53 VCEP in silico worksheet assigns PP3 to c.845G>A, BayesDel is 0.477696, REVEL is 0.887, and SpliceAI predicts no meaningful splice impact.4
Final classification
VUS
PM1PM2PP3
TP53
c.845G>A
p.Arg282Gln
This variant
The TP53 c.845G>A (p.Arg282Gln) variant has been reported in ClinVar with conflicting germline classifications and is also described in somatic cancer literature at a recurrent TP53 hotspot residue.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM1 moderate (+2) + PM2 supporting (+1) + PP3 supporting (+1) = 4 points, which maps to VUS.
Classification rationale
PM1PM2PP3
VUS
TP53 c.845G>A
PM1 + PM2 + PP3
→
VUS
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:11896595 ↗PMID:11920959 ↗PMID:18453682 ↗
4
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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 · 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM1
moderate
Pathogenic
This missense variant affects TP53 codon 282, one of the codons explicitly designated by the TP53 VCEP as a mutational hotspot for PM1 at Moderate strength.
TP53 VCEP PM1 codon list includes codon 282Published somatic/structural literature describes Arg282 as a TP53 hotspot residue
PM2
supporting
Pathogenic
This variant is rare in population databases. In gnomAD v4.1, the overall allele frequency is 5.58e-06, which is below the TP53 PM2 threshold of 3.0e-05, and the highest observed subpopulation frequency is 2.23e-05, which is below the 4.0e-05 subpopulation threshold. gnomAD v2.1 shows 1 allele among 251444 alleles (3.98e-06).
gnomAD v4.1 AF 5.576e-06best subpopulation AF 2.229e-05gnomAD v2.1 AF 3.977e-06
PP3
supporting
Pathogenic
Computational evidence supports a deleterious effect. The TP53 VCEP PP3/BP4 spreadsheet assigns PP3 to c.845G>A; BayesDel is 0.477696, above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.887, and SpliceAI shows no predicted splice effect (max delta score 0.00).
VCEP PP3-BP4 table entry: c.845G>A -> PP3BayesDel 0.477696REVEL 0.887
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No verified TP53 VCEP pathogenic or likely pathogenic variant with the same amino acid change was identified for PS1 assessment.
PS2
No variant-specific confirmed de novo observation with the TP53 point-based requirements was identified.
PS3
TP53 VCEP functional data do not support PS3 for this variant.
PS4
Although PM2_Supporting is met, no variant-specific germline case series with sufficient TP53 PS4 point scoring were identified, so PS4 cannot be assigned.
PM5
No fully verified same-residue TP53 VCEP pathogenic or likely pathogenic comparator set was established from the reviewed materials, so PM5 was not assigned.
PP1
No variant-specific segregation data with enough informative meioses were identified to support PP1.
PP4
No low-variant-allele-fraction blood observation or related mosaicism evidence meeting the TP53 PP4 requirements was identified.
Benign
BA1
Population frequency does not meet the TP53 BA1 threshold.
BS1
Population frequency does not meet the TP53 BS1 threshold.
BS2
No single-source dataset showing the required number of unrelated females age 60 years or older without cancer was identified for this variant.
BS3
TP53 VCEP functional data do not support BS3 for this variant.
BS4
No variant-specific lack-of-segregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were identified.
BP4
Computational evidence does not support BP4.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.57636e-06; MAF= 0.00056%, 9/1613956 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22926e-05; MAF= 0.00223%, 1/44858 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97703e-06; MAF= 0.00040%, 1/251444 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.61979e-05; MAF= 0.00462%, 1/21646 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,613,956
0 hom · FAF 0.00018%
0 hom · FAF 0.00018%
East Asian 1 / 44,858 |
0.0022% |
European (Finnish) 1 / 64,030 |
0.0016% |
African/African American 1 / 74,898 |
0.0013% |
European (non-Finnish) 6 / 1,180,030 |
0.00051% |
+ 6 not observed (Remaining individuals, Admixed American, Amish, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0004%
· 1 / 251,444
0 hom
0 hom
European (Finnish) 1 / 21,646 |
0.0046% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 237956)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.887. BayesDel score = 0.477696.
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; COSV52689673, n = 46 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.
Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstroms resolution.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
10864200 ↗
P53 germline mutations in childhood cancers and cancer risk for carrier individuals.
CLINVAR
11429705 ↗
p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.
CLINVAR
11782540 ↗
A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR