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LYFE SCIENCES
Project: HERA
NM_000546.5:c.221C>T
p.Ala74Val  ·  TP53
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Classification rationale
1

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.

clinvar ↗ hotspots ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:29979965 ↗ PMID:30224644 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.234. BayesDel score = -0.213549.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA74
Hotspots ↗