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.1 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.2 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 BS3.3 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.4
Final classification
Likely Benign
PM2BS3BP4BP6
TP53
c.221C>T
p.Ala74Val
This variant
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.
TP53 VCEP v2.4.0 point-based final classification framework (Tavtigian Bayesian adaptation); total score = -6 points.
Classification rationale
PM2
BS3BP4BP6
Likely Benign
TP53 c.221C>T
PM2 + BS3 + BP4 + BP6
→
Likely Benign
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
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. 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.
gnomAD v4.1 total AF 6.818880612558642e-06grpmax FAF 2.92e-06gnomAD v2.1 total AF 1.0641769655348553e-05
BS3
strong
Benign
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.
Functional worksheet row: A74V | Functional | noLOF | BS3TP53 VCEP functional flowchart accepts eligible functional assay summaries for BS3
BP4
moderate
Benign
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.
PP3/BP4 worksheet row: c.221C>T | p.Ala74Val | Class C0 | -0.213549 | BP4_moderateSpliceAI max delta 0.00REVEL 0.234
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
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.
PS2
No confirmed de novo observation with appropriate parental confirmation and Li-Fraumeni syndrome point assignment was identified for this variant.
PS3
Available TP53 functional evidence does not show loss of function for p.Ala74Val.
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.
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.
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.
PP1
No segregation data were identified for this variant, so cosegregation with Li-Fraumeni syndrome-associated cancers could not be assessed.
PP3
Available computational evidence does not support a damaging effect.
PP4
No phenotype-specific or low-variant-allele-fraction clinical observation data were identified to support TP53-specific PP4 scoring for this variant.
Benign
BA1
Population frequency does not meet the TP53 BA1 threshold.
BS1
Population frequency does not meet the TP53 BS1 threshold.
BS2
No single-source dataset of unaffected older female carriers was identified for this variant, so BS2 could not be assessed.
BS4
No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 could not be assessed.
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= 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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068%
· 11 / 1,613,168
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
European (Finnish) 3 / 64,024 |
0.0047% |
European (non-Finnish) 8 / 1,179,650 |
0.00068% |
+ 8 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0011%
· 3 / 281,908
0 hom
0 hom
European (Finnish) 3 / 25,106 |
0.012% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian)
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
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; COSV53086204, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links