The TP53 c.245C>T (p.Pro82Leu) variant has been reported in ClinVar, where the aggregate classification is Likely Benign with expert panel review.1 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.2 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.3 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.4
Final classification
Likely Benign
PM2BS3BP4BP6
TP53
c.245C>T
p.Pro82Leu
This variant
The TP53 c.245C>T (p.Pro82Leu) variant has been reported in ClinVar, where the aggregate classification is Likely Benign with expert panel review.
TP53 VCEP v2.4.0 CSPEC Tavtigian point-based final-classification framework; BS3_Strong (-4), BP4 (-1), BP6 (-1), and PM2_Supporting (+1) yield a net score of -5 points.
Classification rationale
PM2
BS3BP4BP6
Likely Benign
TP53 c.245C>T
PM2 + BS3 + BP4 + BP6
→
Likely Benign
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
4
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
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 · 13 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
PM2
supporting
Pathogenic
This variant is rare in population databases. The overall allele frequency is 1.99644e-05 in gnomAD v2.1 and 1.11599e-05 in gnomAD v4.1, both below the TP53 VCEP PM2 threshold of 0.00003, and no non-founder ancestry group with multiple alleles exceeds the 0.00004 cutoff, so PM2 is met at supporting strength.
gnomAD v2.1 AF 1.99644e-05.gnomAD v4.1 AF 1.11599e-05.AMR in gnomAD v4.1 has 2 alleles with AF 3.33467e-05
BS3
strong
Benign
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 TP53 protein function.
Functional worksheet row: P82L | Functional | noLOF | BS3.TP53 VCEP functional flowchart supports BS3 for retained function.
BP4
supporting
Benign
Available computational evidence supports a benign interpretation under the TP53 VCEP missense framework. The TP53 PP3/BP4 worksheet lists c.245C>T (p.Pro82Leu) as Class C0 with BayesDel 0.0708215 and assigns BP4, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.57, but the TP53 VCEP precomputed code for this missense change is BP4.
TP53 worksheet entry: c.245C>T | p.Pro82Leu | Class C0 | 0.0708215 | BP4.SpliceAI max delta score 0.00.REVEL score 0.57.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No previously established TP53 VCEP pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed evidence, so PS1 cannot be assigned from the available data.
PS2
No confirmed de novo observation with the TP53 VCEP point-based evidence required for PS2 was identified.
PS3
Available functional evidence does not support a damaging effect.
PS4
No countable affected probands or Li-Fraumeni syndrome point total were identified for this variant, so PS4 cannot be applied even though the population frequency is low enough for PM2_Supporting.
PM1
This missense variant affects codon 82, which is outside the TP53 VCEP codons that qualify directly for PM1 (175, 245, 248, 249, 273, 282), and no verified hotspot evidence showing at least 2 somatic occurrences for this exact amino acid change was identified in the reviewed evidence.
PM5
No reviewed evidence identified previously established TP53 VCEP pathogenic or likely pathogenic missense variants at codon 82 that would support PM5.
PP1
No segregation data with countable meioses were identified for this variant, so PP1 cannot be applied.
PP3
Available computational evidence does not support a damaging effect under the TP53 VCEP in silico framework.
PP4
No blood variant allele fraction or comparable mosaicism data were identified, so the TP53 VCEP PP4 thresholds based on low variant allele fraction observations cannot be evaluated.
Benign
BA1
The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BA1 threshold of 0.001, so BA1 is not met.
BS1
The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BS1 threshold of 0.0003, so BS1 is not met.
BS2
No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be evaluated.
BS4
No segregation study showing lack of segregation with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be evaluated.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0011%
· 18 / 1,612,916
0 hom · FAF 0.00088%
0 hom · FAF 0.00088%
Ashkenazi Jewish 1 / 29,600 |
0.0034% |
Admixed American 2 / 59,976 |
0.0033% |
South Asian 3 / 91,024 |
0.0033% |
African/African American 2 / 74,994 |
0.0027% |
Remaining individuals 1 / 62,420 |
0.0016% |
European (non-Finnish) 9 / 1,179,646 |
0.00076% |
+ 4 not observed (European (Finnish), Amish, East Asian, Middle Eastern)
gnomAD v2.1
0.002%
· 5 / 250,446
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
African/African American 1 / 15,714 |
0.0064% |
South Asian 1 / 30,614 |
0.0033% |
European (non-Finnish) 3 / 113,356 |
0.0026% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.57. BayesDel score = 0.0708215.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links