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
TP53
Final classification
Likely Benign
TP53 c.245C>T · p.Pro82Leu
TP53
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
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 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