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LYFE SCIENCES
Project: HERA
NM_000546.5:c.370T>A
p.Cys124Ser  ·  TP53
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Classification rationale
1

The TP53 c.370T>A (p.Cys124Ser) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classified it as Likely Benign.

clinvar ↗
2

This variant is present at low frequency in gnomAD, including 3 of 1612186 alleles overall in v4.1 and 3 of 74876 alleles in the African/African American population; the subgroup frequency of 0.0000401 is slightly above the TP53 VCEP PM2 multi-allele threshold of less than 0.00004, so PM2 is not met.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

In TP53 VCEP-supported functional datasets, p.Cys124Ser was functional in Kato et al. and showed no loss of function in the Giacomelli and Kotler datasets, supporting BS3.

PMID:12826609 ↗ PMID:29979965 ↗
4

In silico evidence is mixed: the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate to c.370T>A based on Align-GVGD class C65 and BayesDel 0.257897, while SpliceAI is 0.02 and predicts no meaningful splice effect; REVEL is 0.716.

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
—
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= 1.06288e-05; MAF= 0.00106%, 3/282252 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000120395; MAF= 0.01204%, 3/24918 alleles, homozygotes = 0); grpmax FAF= 2.138e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.86083e-06; MAF= 0.00019%, 3/1612186 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00662e-05; MAF= 0.00401%, 3/74876 alleles, homozygotes = 0); grpmax FAF= 1.064e-05.
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 (1 clinical laboratory) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
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 = 0.02). REVEL score = 0.716. BayesDel score = 0.0594274.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueC124
Hotspots ↗