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.1 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.2 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 BS3.3 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 0.716.4
Final classification
Likely Benign
PP3BS3BP6
TP53
c.370T>A
p.Cys124Ser
This variant
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PP3 moderate (+2) + BS3 strong (-4) = -2 points, which maps to Likely Benign.
Classification rationale
PP3
BS3BP6
Likely Benign
TP53 c.370T>A
PP3 + BS3 + BP6
→
Likely Benign
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗
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 · 3 applied · 14 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PP3
moderate
Pathogenic
The TP53 VCEP bioinformatic worksheet assigns PP3_Moderate to c.370T>A. This variant is listed as Align-GVGD class C65 with BayesDel 0.257897, which is above the TP53 PP3_Moderate BayesDel threshold of 0.16. SpliceAI is 0.02, indicating no predicted splice effect, and REVEL is 0.716.
PP3-BP4 worksheet row: c.370T>A / p.Cys124SerAlign-GVGD class C65BayesDel 0.257897
BS3
strong
Benign
In the TP53 VCEP functional worksheet, p.(Cys124Ser) is listed as Functional in Kato et al. and shows no loss of function in the Giacomelli and Kotler datasets. This pattern meets TP53 BS3 for retained function across eligible assays.
Functional worksheet row: C124SKato class: FunctionalGiacomelli class: noLOF
Assessed · not applied
· 7 not met · 7 not assessed
Pathogenic
PS1
No reviewed evidence was identified showing that a different nucleotide change causing the same p.(Cys124Ser) protein effect has already been classified as pathogenic or likely pathogenic under the TP53 VCEP rules.
PS2
No confirmed de novo occurrence with the phenotypic detail required for TP53 PS2 scoring was identified.
PS3
Available TP53 functional evidence does not support a damaging effect.
PS4
No TP53 case-level PS4 point evidence was identified, and PM2_Supporting is not met because the highest gnomAD v4.1 African/African American frequency is 0.0000401 (3/74876), which is slightly above the TP53 VCEP multi-allele subgroup threshold of less than 0.00004.
PM1
This missense variant is not at one of the TP53 VCEP hotspot codons 175, 245, 248, 249, 273, or 282, and Cancer Hotspots did not identify p.(Cys124Ser) as a statistically significant hotspot variant.
PM2
This variant is present in gnomAD.
PM5
No reviewed evidence was identified showing that codon 124 has a different TP53 missense variant already classified as pathogenic or likely pathogenic under the TP53 VCEP rules at the level needed for PM5.
PP1
No segregation data were identified, so there is no evidence to score PP1.
PP4
No case-specific blood variant allele fraction data or constitutional mosaicism observations were identified to support TP53 PP4.
Benign
BA1
This variant does not meet BA1 because the highest observed gnomAD filtering allele frequency is far below the TP53 BA1 threshold of 0.001.
BS1
This variant does not meet BS1 because the highest observed gnomAD filtering allele frequency is below the TP53 BS1 threshold of 0.0003.
BS2
No evidence was identified showing this variant in unrelated females aged 60 years or older without cancer from a single source, so BS2 cannot be assessed.
BS4
No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified.
BP4
BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate, not BP4, to c.370T>A.
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= 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,612,186
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 3 / 74,876 |
0.004% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0011%
· 3 / 282,252
0 hom · FAF 0.0021%
0 hom · FAF 0.0021%
African/African American 3 / 24,918 |
0.012% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), 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 (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 = 0.02). REVEL score = 0.716. BayesDel score = 0.0594274.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers 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
Sources & reference links