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
TP53
Final classification
Likely Benign
TP53 c.221C>T · p.Ala74Val
TP53
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
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= 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.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:29979965
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:30224644
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links