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LYFE SCIENCES
Project: HERA
NM_000546.5:c.245C>T
p.Pro82Leu  ·  TP53
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Classification rationale
1

The TP53 c.245C>T (p.Pro82Leu) variant has been reported in ClinVar, where the aggregate classification is Likely Benign with expert panel review.

clinvar ↗
2

This variant is present at very low frequency in gnomAD v2.1 and v4.1 (overall AF 1.99644e-05 and 1.11599e-05; grpmax FAF 7.03e-06 and 8.76e-06), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003 overall and below 0.00004 in any non-founder ancestry group with multiple alleles.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3 and the summarized assay interpretation is functional with no loss-of-function, supporting retained protein function.

4

Computational assessment under the TP53 VCEP missense framework lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, while SpliceAI predicts no splice impact (max delta 0.00); REVEL is 0.57 but does not override the TP53 VCEP benign computational assignment for this variant.

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
—
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= 1.99644e-05; MAF= 0.00200%, 5/250446 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.36375e-05; MAF= 0.00636%, 1/15714 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.11599e-05; MAF= 0.00112%, 18/1612916 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37838e-05; MAF= 0.00338%, 1/29600 alleles, homozygotes = 0); grpmax FAF= 8.76e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.57. BayesDel score = 0.0708215.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53209087, n = 11 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP82
Hotspots ↗