c.413C>A (p.Ala138Asp) in TP53 is a missense variant in exon 5. It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).1 In silico predictions are consistent with a deleterious effect: aGVGD Class C65, BayesDel 0.540498, REVEL 0.901, and SpliceAI predicts no splicing impact (max delta 0.01). The TP53 VCEP assigns PP3_moderate.2 Functional data from the TP53 VCEP Functional-worksheet (Supplementary Table S3) assign 'No evidence' to p.Ala138Asp: Kato shows partially functional, Funk shows LOF, but Giacomelli and Kotler show noLOF. Neither PS3 nor BS3 criteria are met.3 The variant is not located in a VCEP-specified PM1 hotspot codon (175, 245, 248, 249, 273, 282), and the exact variant is not listed in cancerhotspots.org (PM1 not met). This variant has been reported in ClinVar as Uncertain Significance by the ClinGen TP53 Variant Curation Expert Panel (ClinVar ID: 528270) and has been observed 3 times in somatic cancers (COSMIC COSV53502932).4 PVS1, PS5, PM6, PP2, PP5, BP1, BP2, BP5, BP6, and BP7 are not applicable per the TP53 VCEP v2.4.0 specifications or by variant type. PS1, PS2, PS4, PM5, PP1, PP4, BS2, BS4, and BS5 remain not assessed due to insufficient clinical data.5
TP53
Final classification
VUS
TP53 c.413C>A · p.Ala138Asp
TP53
c.413C>A (p.Ala138Asp) in TP53 is a missense variant in exon 5. It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + PP3 moderate (+2) = 3 points, which maps to VUS.
Classification rationale
PM2PP3
VUS
TP53 c.413C>A
PM2 + PP3
→
VUS
2
vcep_pp3_bp4_codesrevelbayesdelspliceai ↗
3
vcep_functional_worksheetPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
5
cspec ↗
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1 and v4.1 (allele count = 0), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.003% (0.00003) in large population databases.
Absent from gnomAD v2.1 (AC=0)Absent from gnomAD v4.1 (AC=0)
✓
PP3
moderate
Pathogenic
The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns PP3_moderate to c.413C>A (p.Ala138Asp) based on aGVGD Class C65 and BayesDel score 0.540498. SpliceAI max delta is 0.01, indicating no predicted splicing impact, which does not alter the missense-based bioinformatic code. REVEL score is 0.901, consistent with a deleterious prediction.
VCEP PP3-BP4-codes: PP3_moderateaGVGD Class C65BayesDel: 0.540498
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change resulting in the same amino acid substitution (p.Ala138Asp) that has been classified as pathogenic or likely pathogenic per TP53 VCEP specifications.
PS2
No de novo observations have been reported for this variant.
PS3
The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp.
PS4
No proband-level data with LFS cancer phenotypes are available for point scoring under the TP53 VCEP PS4 point system.
PM1
Codon 138 is not among the TP53 VCEP-specified PM1 hotspot codons (175, 245, 248, 249, 273, 282).
PM5
The pm5_candidates search found no same-residue comparator variants with definitive VCEP pathogenic/likely pathogenic classification.
PP1
No cosegregation data are available for this variant.
PP4
No proband-level variant allele fraction (VAF) data are available.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0).
BS1
The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0).
BS2
No data on unrelated females who have reached ≥60 years of age without cancer are available.
BS3
The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp.
BS4
No segregation data are available to assess lack of segregation in affected family members.
BP4
BayesDel score is 0.540498, which is well above the BP4 thresholds (BP4_Moderate requires ≤ -0.008; BP4_Supporting requires < 0.16).
BP5
No evidence of an alternative molecular basis for disease has been identified.
N/A · 8
PVS1 · PM6 · PP2 · PP5 · BP1 · BP2 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 528270)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.901. BayesDel score = 0.540498.
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
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53502932, n = 3 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
8023157 ↗
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.
ONCOKB
12826609 ↗
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
CLINVAR
29979965 ↗
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
CLINVAR
9472631 ↗
Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR