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LYFE SCIENCES
Project: HERA
NM_000546.5:c.581T>G
p.Leu194Arg  ·  TP53
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Classification rationale
1

The TP53 c.581T>G (p.Leu194Arg; p.L194R) variant has curated somatic cancer literature in OncoKB and is reported in ClinVar as Pathogenic, including by the ClinGen TP53 Variant Curation Expert Panel.

oncokb ↗ clinvar ↗
2

This variant is rare in population databases, with 1/1614188 alleles in gnomAD v4.1 (AF 6.20e-07) and 1/251486 alleles in gnomAD v2.1 (AF 3.98e-06), which is below the TP53 PM2 threshold of 0.00003.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

In the TP53 VCEP functional worksheet, p.Leu194Arg is listed as non-functional in the Kato assay and as loss-of-function in the other eligible assay categories reviewed, supporting PS3.

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

In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate; BayesDel is 0.582962, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect without evidence for a splice-based mechanism.

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
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Gaps remaining
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Rule
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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= 3.97636e-06; MAF= 0.00040%, 1/251486 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19507e-07; MAF= 0.00006%, 1/1614188 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
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 = 0.13). REVEL score = 0.933. BayesDel score = 0.582962.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52679257, n = 156 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueL194
Hotspots ↗