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
TP53
Final classification
Likely Benign
TP53 c.370T>A · p.Cys124Ser
TP53
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
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 3 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= 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.
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
Sources & reference links