TP53c.221C>TLikely benign

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Variant interpretation report

TP53 c.221C>T, p.(Ala74Val)

NM_000546.5:c.221C>T NP_000537.3:p.(Ala74Val) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (benign) · 1 moderate (benign) · 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is rare in population databases. In gnomAD v4.1 it is present at 11/1613168 alleles (AF 0.00068%; grpmax FAF 2.92e-06), and in gnomAD v2.1 at 3/281908 alleles (AF 0.00106%). These values are below the TP53 PM2 threshold of 0.003%, and the higher Finnish frequency is in a founder population excluded by the TP53 VCEP rule.
BS3 (strong): In TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary. This supports BS3 under the TP53 functional framework.
BP4 (moderate): Computational evidence supports a benign interpretation. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.221C>T, with BayesDel -0.213549, which is at or below the TP53 BP4_Moderate threshold, and SpliceAI predicts no significant splice impact (max delta 0.00). REVEL is 0.234 and does not provide a strong deleterious signal.
BP6 (supporting): Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.

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: 1 Benign evidence criteria: 3

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is rare in population databases. In gnomAD v4.1 it is present at 11/1613168 alleles (AF 0.00068%; grpmax FAF 2.92e-06), and in gnomAD v2.1 at 3/281908 alleles (AF 0.00106%). These values are below the TP53 PM2 threshold of 0.003%, and the higher Finnish frequency is in a founder population excluded by the TP53 VCEP rule.

Benign criteria applied · 3

BS3Strong

BS3 · strong

In TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary. This supports BS3 under the TP53 functional framework.

BP4Moderate

BP4 · moderate

Computational evidence supports a benign interpretation. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.221C>T, with BayesDel -0.213549, which is at or below the TP53 BP4_Moderate threshold, and SpliceAI predicts no significant splice impact (max delta 0.00). REVEL is 0.234 and does not provide a strong deleterious signal.

BP6Supporting

BP6 · supporting

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.

Recorded classification: Likely benign

TP53 VCEP v2.4.0 point-based final classification framework (Tavtigian Bayesian adaptation); total score = -6 points.

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

11 / 1,613,168 alleles

gnomAD v4.1: 11 / 1,613,168 alleles. Recorded AF 6.81888e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.06418e-05; MAF= 0.00106%, 3/281908 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000119493; MAF= 0.01195%, 3/25106 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Applied · BP6 → ClinVar ↗

Functional evidence

Statement recorded

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.

Applied · BS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 4 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The TP53 c.221C>T (p.Ala74Val) variant has been reported in ClinVar, including a Likely Benign classification from the ClinGen TP53 Variant Curation Expert Panel, and available hotspot review did not identify it as a recurrent TP53 hotspot.

This variant is rare in gnomAD v4.1 (11/1613168 alleles; AF 0.00068%; grpmax FAF 2.92e-06) and gnomAD v2.1 (3/281908 alleles; AF 0.00106%), which is below the TP53 PM2 threshold of 0.003% and below the BS1 and BA1 thresholds.

In TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary, supporting BS3.

TP53 VCEP bioinformatic calibration assigns BP4_moderate for c.221C>T; BayesDel is -0.213549, SpliceAI max delta is 0.00, and REVEL is 0.234, which together do not support a damaging computational effect.

Met · 4

PM2 SupportingThis variant is rare in population databases. In gnomAD v4.1 it is present at 11/1613168 alleles (AF 0.00068%; grpmax FAF 2.92e-06), and in gnomAD v2.1 at 3/281908 alleles (AF 0.00106%). These values are below the TP53 PM2 threshold of 0.003%, and the higher Finnish frequency is in a founder population excluded by the TP53 VCEP rule. Details ▾Hide ▴

Rule

PM2_Supporting

Evidence considered

gnomAD v4.1 total AF 6.818880612558642e-06
grpmax FAF 2.92e-06
gnomAD v2.1 total AF 1.0641769655348553e-05
Finnish founder population has highest observed frequency

Sources

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BS3 StrongIn TP53 functional data summarized by the TP53 VCEP, p.Ala74Val was functional and showed no loss of function in the available eligible assay summary. This supports BS3 under the TP53 functional framework. Details ▾Hide ▴

Rule

BS3

Evidence considered

Functional worksheet row: A74V | Functional | noLOF | BS3
TP53 VCEP functional flowchart accepts eligible functional assay summaries for BS3

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

BP4 ModerateComputational evidence supports a benign interpretation. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.221C>T, with BayesDel -0.213549, which is at or below the TP53 BP4_Moderate threshold, and SpliceAI predicts no significant splice impact (max delta 0.00). REVEL is 0.234 and does not provide a strong deleterious signal. Details ▾Hide ▴

Rule

BP4_Moderate

Evidence considered

PP3/BP4 worksheet row: c.221C>T | p.Ala74Val | Class C0 | -0.213549 | BP4_moderate
SpliceAI max delta 0.00
REVEL 0.234

Sources

vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BP6 SupportingExpert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP6 as not applicable
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

PS3 Available TP53 functional evidence does not show loss of function for p.Ala74Val. The TP53 VCEP functional worksheet summarizes this variant as functional with no loss of function, so PS3 is not supported. Details ▾Hide ▴

Evidence considered

Functional worksheet row: A74V | Functional | noLOF | BS3
TP53 VCEP functional flowchart directs PS3/BS3 use from eligible assays

Sources

vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

PP3 Available computational evidence does not support a damaging effect. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate, not PP3, for c.221C>T; BayesDel is -0.213549, SpliceAI predicts no significant splice impact (max delta 0.00), and REVEL is 0.234. Details ▾Hide ▴

Evidence considered

PP3/BP4 worksheet row: c.221C>T | p.Ala74Val | Class C0 | -0.213549 | BP4_moderate
SpliceAI max delta 0.00
REVEL 0.234

Sources

vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BA1 Population frequency does not meet the TP53 BA1 threshold. The gnomAD v4.1 grpmax FAF is 2.92e-06, which is below the BA1 cutoff of 0.001. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF 2.92e-06

Sources

cspec ↗gnomad_v4 ↗

BS1 Population frequency does not meet the TP53 BS1 threshold. The gnomAD v4.1 grpmax FAF is 2.92e-06, which is below the BS1 cutoff of 0.0003. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF 2.92e-06

Sources

cspec ↗gnomad_v4 ↗

Not assessed · 9 · no assessment recorded

PS1 No evidence was identified showing that a different nucleotide change produces the same amino acid substitution and has already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP PS1 requires a previously classified pathogenic or likely pathogenic same-amino-acid substitution

Still missing

No qualifying same-amino-acid pathogenic comparison was identified.

Sources

cspec ↗

PS2 No confirmed de novo observation with appropriate parental confirmation and Li-Fraumeni syndrome point assignment was identified for this variant. Details ▾Hide ▴

Evidence considered

TP53 VCEP uses point-based de novo scoring for PS2

Still missing

No confirmed de novo case with parental testing was identified.
No TP53 VCEP point-based PS2 evidence was available for this variant.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PS4 No case-level evidence was identified to assign TP53 Li-Fraumeni syndrome points for affected probands carrying this variant, so enrichment in affected individuals could not be established. Details ▾Hide ▴

Evidence considered

TP53 VCEP PS4 requires point-based affected-case evidence

Still missing

No qualifying proband point total was identified.
No case-control or point-based TP53 VCEP PS4 evidence was available for this variant.

Sources

cspec ↗vcep_ps4_points_table

PM1 Available hotspot review did not identify p.Ala74Val as a statistically significant TP53 hotspot, but the hotspot review was flagged for human confirmation, so PM1 is not assigned at this time. Details ▾Hide ▴

Evidence considered

Cancer Hotspots review found no hotspot row for residue A74 and flagged the result for human review

Still missing

Hotspot review was flagged for human confirmation.
No verified residue-specific recurrence count meeting TP53 PM1 thresholds was identified.

Sources

cspec ↗hotspots ↗

PM5 No reviewed evidence was identified showing that other missense substitutions at codon 74 have already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP PM5 depends on previously classified alternate missense variants at the same residue

Still missing

No qualifying pathogenic or likely pathogenic alternate missense variant at residue 74 was identified.

Sources

cspec ↗

PP1 No segregation data were identified for this variant, so cosegregation with Li-Fraumeni syndrome-associated cancers could not be assessed. Details ▾Hide ▴

Evidence considered

TP53 VCEP PP1 requires informative meioses across affected relatives

Still missing

No pedigree or meiosis count was identified.

Sources

cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application

PP4 No phenotype-specific or low-variant-allele-fraction clinical observation data were identified to support TP53-specific PP4 scoring for this variant. Details ▾Hide ▴

Evidence considered

TP53 VCEP PP4 is based on specific clinical observations and variant allele fraction context

Still missing

No qualifying TP53 VCEP PP4 clinical observation was identified.

Sources

cspec ↗

BS2 No single-source dataset of unaffected older female carriers was identified for this variant, so BS2 could not be assessed. Details ▾Hide ▴

Evidence considered

TP53 VCEP BS2 requires unaffected older female carriers from a single source

Still missing

No qualifying unaffected carrier count from a single source was identified.

Sources

cspec ↗

BS4 No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be assessed. Details ▾Hide ▴

Evidence considered

TP53 VCEP BS4 requires lack of segregation in affected family members

Still missing

No nonsegregation pedigree data were identified.

Sources

cspec ↗

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant, not a nonsense, frameshift, or canonical +/-1,2 splice variant, and SpliceAI predicts no significant splice impact (max delta score 0.00). Available evidence does not support a loss-of-function mechanism eligible for PVS1. Details ▾Hide ▴

Evidence considered

NM_000546.5:c.221C>T encodes p.(Ala74Val)
TP53-specific PVS1 framework applies to null/splice classes
SpliceAI max delta score 0.00
Generic PVS1 scaffold states this variant is outside default null-variant buckets

Sources

cspec ↗vcep_pvs1_flowchartpvs1_gene_contextpvs1_variant_assessmentspliceai ↗

PM3 N/APM3 is not used for TP53 in this framework because TP53-related disease is not assessed here as a recessive condition requiring trans observations. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM3 as not applicable

Sources

cspec ↗

PM4 N/APM4 is not applicable because this variant is a missense substitution, not a protein length-changing in-frame insertion/deletion or stop-loss variant. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM4 as not applicable for this framework

Sources

cspec ↗

PM6 N/APM6 is not used in this TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PM6 as not applicable

Sources

cspec ↗

PP2 N/APP2 is not used for TP53 in this framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP2 as not applicable

Sources

cspec ↗

PP5 N/APP5 is not used in this TP53 VCEP framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks PP5 as not applicable

Sources

cspec ↗

BP1 N/ABP1 is not used for TP53 in this framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP1 as not applicable

Sources

cspec ↗

BP2 N/ABP2 is not used for TP53 in this framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP2 as not applicable

Sources

cspec ↗

BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP3 as not applicable

Sources

cspec ↗

BP5 N/ABP5 is not used for TP53 in this framework. Details ▾Hide ▴

Evidence considered

TP53 VCEP marks BP5 as not applicable

Sources

cspec ↗

BP7 N/ABP7 is for synonymous or qualifying intronic variants. This variant is missense, so BP7 does not apply. Details ▾Hide ▴

Evidence considered

Variant consequence is missense p.(Ala74Val)

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.221C>T
Protein (HGVS p.): NP_000537.3:p.(Ala74Val)
GRCh38: chr17:7676148 G>A
GRCh37: chr17:7579466 G>A

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 11 / 1,613,168 alleles AF 6.82e-06 · 0 homozygotes · FAF 2.92e-06

gnomAD v2.1 3 / 281,908 alleles AF 1.06e-05 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 6.8e-06 · 11 / 1,613,168 alleles · 0 hom · FAF 2.9e-06

European (Finnish)3 / 64,024	4.7e-05
European (non-Finnish)8 / 1,179,650	6.8e-06

0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 1.1e-05 · 3 / 281,908 alleles · 0 hom

European (Finnish)3 / 25,106

0.00012

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.81888e-06; MAF= 0.00068%, 11/1613168 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.68574e-05; MAF= 0.00469%, 3/64024 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

BP4_Moderate

Evidence considered

PP3/BP4 worksheet row: c.221C>T | p.Ala74Val | Class C0 | -0.213549 | BP4_moderate
SpliceAI max delta 0.00
REVEL 0.234

Sources

vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

Evidence considered

PP3/BP4 worksheet row: c.221C>T | p.Ala74Val | Class C0 | -0.213549 | BP4_moderate
SpliceAI max delta 0.00
REVEL 0.234

Sources

vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

BP7 N/ABP7 is for synonymous or qualifying intronic variants. This variant is missense, so BP7 does not apply. Details ▾Hide ▴

Evidence considered

Variant consequence is missense p.(Ala74Val)

Sources

cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.234. BayesDel score = -0.213549.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 11 / 1,613,168 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (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 = 0.234. BayesDel score = -0.213549.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53086204, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.