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LYFE SCIENCES
Project: HERA
NM_000546.5:c.490A>G
p.Lys164Glu  ·  TP53
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Classification rationale
1

The TP53 c.490A>G (p.Lys164Glu) variant has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen TP53 Variant Curation Expert Panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614174 alleles; AF 6.20e-07), which is below the TP53 PM2 threshold of 0.00003.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In published TP53 functional studies summarized by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function across other eligible assays, supporting PS3 at strong strength.

PMID:12826609 ↗ PMID:29979965 ↗ PMID:30224644 ↗
4

TP53 VCEP computational tables assign PP3 to this missense change; BayesDel is 0.557217 and REVEL is 0.875, while SpliceAI predicts no significant splice impact (max delta score 0.00).

spliceai ↗
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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19512e-07; MAF= 0.00006%, 1/1614174 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 246416)
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 = 0.875. BayesDel score = 0.557217.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52728094, n = 34 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueK164
Hotspots ↗