About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.413C>A, p.(Ala138Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Moderate
PP3 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53502932, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 6 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
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.
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.
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).
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.
No criteria match.
Met · 2
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0)
- Absent from gnomAD v4.1 (AC=0)
Sources
PP3 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: PP3_moderate
- aGVGD Class C65
- BayesDel: 0.540498
- REVEL: 0.901
- SpliceAI max delta: 0.01 (no splicing effect)
Sources
Not met · 6 · evaluated, threshold not reached
PS3 The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp. Kato assay shows partially functional (not non-functional), and the majority of available assays do not show loss of function: Funk=LOF, Giacomelli=noLOF, Kotler=noLOF (1/3 LOF is not a majority). PS3 requires non-functional on Kato, and PS3_Moderate requires LOF by the majority of assays; neither condition is met. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet code: No evidence
- Kato: Partially functional
- Funk: LOF
- Giacomelli: noLOF
- Kotler: noLOF
Sources
PM1 Codon 138 is not among the TP53 VCEP-specified PM1 hotspot codons (175, 245, 248, 249, 273, 282). The exact variant p.Ala138Asp is not listed in cancerhotspots.org, precluding the alternate cancerhotspots-based PM1 route which requires ≥10 somatic occurrences for the same amino acid change. Details ▾Hide ▴
Evidence considered
- Codon 138 not in VCEP PM1 codon list
- Exact variant A138D not listed in cancerhotspots.org
BA1 The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0). The TP53 VCEP BA1 threshold requires a filtering allele frequency ≥0.001 (0.1%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0). The TP53 VCEP BS1 threshold requires a filtering allele frequency ≥0.0003 in a continental subpopulation. Details ▾Hide ▴
BS3 The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp. BS3 requires functional on Kato data AND no LOF by the majority of available assays; Kato shows partially functional (not functional). BS3_Supporting requires partially functional on Kato AND no LOF by all available assays, but Funk shows LOF, so this is not met. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet code: No evidence
- Kato: Partially functional
- Funk: LOF
- Giacomelli: noLOF
- Kotler: noLOF
Sources
BP4 BayesDel score is 0.540498, which is well above the BP4 thresholds (BP4_Moderate requires ≤ -0.008; BP4_Supporting requires < 0.16). SpliceAI max delta is 0.01 (no predicted splicing impact), but the BayesDel score is not in the benign range. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.540498 (far above BP4 thresholds)
- SpliceAI max delta: 0.01
Sources
Not assessed · 9 · no assessment recorded
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. Details ▾Hide ▴
Still missing
- No alternate nucleotide change producing p.Ala138Asp with a confirmed VCEP P/LP classification was identified.
PS2 No de novo observations have been reported for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo data available for this variant.
PS4 No proband-level data with LFS cancer phenotypes are available for point scoring under the TP53 VCEP PS4 point system. PS4 requires counting probands with strongly or moderately associated LFS cancers per the PS4-Points-Table. Details ▾Hide ▴
Still missing
- No proband-level clinical data available for PS4 scoring.
PM5 The pm5_candidates search found no same-residue comparator variants with definitive VCEP pathogenic/likely pathogenic classification. While A138P has PS3 and A138V has PS3_Moderate in the Functional-worksheet, the full VCEP classification (pathogenic vs. likely pathogenic) for these comparator variants is not established in the available evidence. Details ▾Hide ▴
Evidence considered
- Same-residue variants A138P (PS3) and A138V (PS3_Moderate) identified but full VCEP classification not established.
Still missing
- Full VCEP classification of other A138 missense variants needed to apply PM5.
Sources
vcep_functional_worksheet
PP1 No cosegregation data are available for this variant. PP1 requires observation of cosegregation in 3-4 meioses (Supporting), 5-6 meioses (Moderate), or ≥7 meioses across >1 family (Strong). Details ▾Hide ▴
Still missing
- No segregation data available.
PP4 No proband-level variant allele fraction (VAF) data are available. PP4 requires observation of the variant with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate). Details ▾Hide ▴
Still missing
- No VAF data from proband testing available.
BS2 No data on unrelated females who have reached ≥60 years of age without cancer are available. BS2 requires ≥2 such individuals from a single source (Supporting), 4-7 (Moderate), or ≥8 (Strong). Details ▾Hide ▴
Still missing
- No data on cancer-free females ≥60 years of age available.
BS4 No segregation data are available to assess lack of segregation in affected family members. BS4 requires absence of segregation with LFS-associated cancers. Details ▾Hide ▴
Still missing
- No segregation data available.
BP5 No evidence of an alternative molecular basis for disease has been identified. BP5 is designated as 'Not Applicable' by the TP53 VCEP v2.4.0. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution (p.Ala138Asp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice sites, initiation codon, or gene deletions) and does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- PVS1 decision tree not applicable.
PM6 VCEPThe ClinGen TP53 VCEP specifications designate PM6 as 'Not Applicable' for this gene. Details ▾Hide ▴
PP2 VCEPThe ClinGen TP53 VCEP specifications designate PP2 as 'Not Applicable' for this gene. Details ▾Hide ▴
PP5 VCEPThe ClinGen TP53 VCEP specifications designate PP5 as 'Not Applicable for this VCEP' per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP1 VCEPThe ClinGen TP53 VCEP specifications designate BP1 as 'Not Applicable' for this gene. Details ▾Hide ▴
BP2 VCEPThe ClinGen TP53 VCEP specifications designate BP2 as 'Not Applicable' for this gene. Details ▾Hide ▴
BP6 VCEPThe ClinGen TP53 VCEP specifications designate BP6 as 'Not Applicable' for this gene. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) or intronic variants. This is a missense variant (c.413C>A, p.Ala138Asp) and BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable.
PS5 N/APS5 applies to recessive disorders where a different pathogenic variant is observed in trans. TP53-associated Li-Fraumeni syndrome is autosomal dominant; PS5 is not applicable. Details ▾Hide ▴
Evidence considered
- TP53 is an autosomal dominant disease gene.
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.413C>A
- Protein (HGVS p.)
- NP_000537.3:p.(Ala138Asp)
- GRCh38
- chr17:7675199 G>T
- GRCh37
- chr17:7578517 G>T
- ClinVar
- 956854, 528270
- COSMIC
- COSV53502932
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.
TP53NM_000546.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.901
- BayesDel
- 0.540
How the predictions were used
PP3 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: PP3_moderate
- aGVGD Class C65
- BayesDel: 0.540498
- REVEL: 0.901
- SpliceAI max delta: 0.01 (no splicing effect)
Sources
BP4 BayesDel score is 0.540498, which is well above the BP4 thresholds (BP4_Moderate requires ≤ -0.008; BP4_Supporting requires < 0.16). SpliceAI max delta is 0.01 (no predicted splicing impact), but the BayesDel score is not in the benign range. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.540498 (far above BP4 thresholds)
- SpliceAI max delta: 0.01
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants. This is a missense variant (c.413C>A, p.Ala138Asp) and BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.901. BayesDel score = 0.540498.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 11900253 ↗Rescuing the function of mutant p53.No paper-specific finding is recorded.
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PMID 8023157 ↗Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.No paper-specific finding is recorded.
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PMID 12826609 ↗Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.Kato S et al. · 2003No paper-specific finding is recorded.
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PMID 29979965 ↗A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.Kotler E et al. · 2018No paper-specific finding is recorded.
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PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.Giacomelli AO et al. · 2018No paper-specific finding is recorded.
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PMID 9472631 ↗Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene.Gorgoulis VG et al. · 1998No paper-specific finding is recorded.
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
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PMID 20301488 ↗Li-Fraumeni Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/528270/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578517-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675199-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.413C…
- OncoKB ↗www.oncokb.org/gene/TP53/A138D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121521262
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53502932, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.