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LYFE SCIENCES
Project: HERA
NM_000546.6:c.845G>A
p.Arg282Gln  ·  TP53
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Classification rationale
1

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.

clinvar ↗ oncokb ↗ PMID:18453682 ↗ PMID:26619011 ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

PMID:11896595 ↗ PMID:11920959 ↗ PMID:18453682 ↗
4

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.

spliceai ↗ cspec ↗
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
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
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 = 0.00). REVEL score = 0.887. BayesDel score = 0.477696.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52689673, n = 46 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueR282
Hotspots ↗