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
TP53
Final classification
VUS
TP53 c.845G>A · p.Arg282Gln
TP53
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
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 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
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. 8 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:18453682
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
PMID PMID:26619011
Found
Structured finding pending for this record — see source link.
Applied to
→PM1 supports · met
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
18453682 ↗
Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstroms resolution.
ONCOKB
26619011 ↗
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
ONCOKB
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