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
TP53
Final classification
Likely Pathogenic
TP53 c.581T>G · p.Leu194Arg
TP53
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
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · 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.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:29979965
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:30224644
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links