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.1 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 0.00003.2 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 PS3.3 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.4
Final classification
Likely Pathogenic
PS3PM2PP3PP5
TP53
c.581T>G
p.Leu194Arg
This variant
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 8 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PP3PP5
Likely Pathogenic
TP53 c.581T>G
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
3
vcep_functional_worksheetPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗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_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
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, with a pre-assigned PS3 code. This supports a damaging effect on TP53 protein function.
Functional worksheet row: L194R | NA | Non-functional | LOF | LOF | LOF | NA | PS3.TP53 VCEP functional flowchart designates these assay patterns for PS3/BS3 application.
PM2
supporting
review
Pathogenic
This variant is rare in population databases. In gnomAD v4.1 it is present in 1/1,614,188 alleles (AF 6.20e-07), and in gnomAD v2.1 it is present in 1/251,486 alleles (AF 3.98e-06), both below the TP53 PM2 threshold of 0.00003.
gnomAD v4 total AF 6.195065258817436e-07.gnomAD v2 total AF 3.976364489474563e-06.
PP3
moderate
review
Pathogenic
In the TP53 VCEP bioinformatic worksheet, c.581T>G is assigned PP3_moderate. BayesDel is 0.582962, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.933, and SpliceAI shows no significant predicted splice effect (max delta score 0.13), supporting a damaging missense effect rather than a splicing mechanism.
PP3-BP4 worksheet row: c.581T>G | p.Leu194Arg | Class C65 | 0.582962 | PP3_moderate | 0.13.REVEL score 0.933.SpliceAI max delta score 0.13.
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PVS1
This missense variant is not a nonsense, frameshift, canonical +/-1,2 splice, or other null variant, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.13).
PS1
PS1 requires a different nucleotide change that results in the same amino acid substitution and has a TP53 VCEP pathogenic assertion.
PS2
No confirmed de novo observation with the TP53-specific point-based cancer criteria was identified, so PS2 was not assessed.
PS4
The population data support PM2_Supporting, but no proband-level Li-Fraumeni syndrome point data or affected-case series were identified to score PS4 under the TP53 VCEP framework, so PS4 was not assessed.
PM1
Although this variant has curated somatic cancer literature and recurrent somatic observation in cancer resources, a verified TP53 Cancer Hotspots hotspot assignment for codon 194 or for p.Leu194Arg was not established from the reviewed hotspot evidence.
PM5
PM5 requires a different missense change at the same residue with a prior TP53 VCEP pathogenic or likely pathogenic assertion.
PP1
No segregation data with informative meioses were identified for this variant, so PP1 was not assessed.
PP4
TP53 PP4 is based on low-variant-allele-fraction observations in the appropriate clinical context.
Benign
BA1
This variant is far below the TP53 BA1 threshold of 0.001.
BS1
This variant is below the TP53 BS1 threshold.
BS2
No single-source cohort showing unaffected women age 60 years or older carrying this variant was identified, so BS2 was not assessed.
BS3
Available functional evidence does not support retained TP53 function.
BS4
No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not assessed.
BP4
Available computational evidence does not support a benign prediction.
N/A · 10
PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,188
0 hom
0 hom
Ashkenazi Jewish 1 / 29,606 |
0.0034% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 251,486
0 hom
0 hom
Ashkenazi Jewish 1 / 10,080 |
0.0099% |
+ 7 not observed (African/African American, Admixed American, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.933. BayesDel score = 0.582962.
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; COSV52679257, n = 156 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links