About TP53
No gene-level summary was recorded for this case.
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Variant interpretation report
TP53 c.370T>A, p.(Cys124Ser)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PP3Moderate
PP3 · moderate
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.
Benign criteria applied · 2
BS3Strong
BS3 · strong
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.
BP6Supporting
BP6 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.
Recorded classification: 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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,612,186 alleles
gnomAD v4.1: 3 / 1,612,186 alleles. Recorded AF 1.86083e-06. Recorded homozygote count 0.
gnomAD 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.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 3
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate for missense variants: Align-GVGD class C65 and BayesDel >=0.16.
Evidence considered
- PP3-BP4 worksheet row: c.370T>A / p.Cys124Ser
- Align-GVGD class C65
- BayesDel 0.257897
- preliminary code PP3_moderate
- SpliceAI max delta 0.02
- REVEL 0.716
Sources
BS3 StrongIn 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. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires functional or partially functional evidence with no loss of function across eligible assays, as specified by the TP53 functional framework.
Evidence considered
- Functional worksheet row: C124S
- Kato class: Functional
- Giacomelli class: noLOF
- Kotler class: noLOF
- preliminary functional code: BS3
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗
Not met · 7 · evaluated, threshold not reached
PS3 Available TP53 functional evidence does not support a damaging effect. In the TP53 VCEP functional worksheet, p.(Cys124Ser) is listed as Functional in the Kato dataset and noLOF in the Giacomelli and Kotler datasets, so PS3 is not met. Details ▾Hide ▴
Rule
TP53 VCEP PS3 requires non-functional or partially functional evidence consistent with loss of function across eligible assays.
Evidence considered
- Functional worksheet row: C124S
- Kato class: Functional
- Giacomelli class: noLOF
- Kotler class: noLOF
- preliminary functional code: BS3
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗
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. Details ▾Hide ▴
Rule
TP53 VCEP PS4 is point based and requires qualifying affected-individual evidence; application requires PM2_Supporting first.
Evidence considered
- no PS4 point-based case evidence identified
- PM2_Supporting prerequisite not met
- gnomAD v4.1 African/African American AF 0.0000401 (3/74876)
Still missing
- No proband point data were available.
- Independent germline case observations with TP53 PS4 scoring would be needed.
Sources
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. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to specified hotspot codons or exact amino acid changes with sufficient somatic recurrence.
Evidence considered
- codon 124 is outside the TP53 VCEP hotspot codon list
- Cancer Hotspots: no hotspot row found
Still missing
- Cancer Hotspots screenshot review was flagged for human review
- although no hotspot row was visible.
Sources
PM2 This variant is present in gnomAD. In v4.1, the highest observed frequency is 0.0000401 (3/74876) in the African/African American population, which is slightly above the TP53 VCEP multi-allele subgroup threshold of less than 0.00004 for PM2_Supporting, so PM2 is not met. Details ▾Hide ▴
Rule
TP53 VCEP PM2 is supporting only and requires AF <0.00003 overall and, if multiple alleles are present in a subgroup, AF <0.00004 in that subgroup.
Evidence considered
- gnomAD v4.1 total AF 1.86083e-06 (3/1612186)
- highest subgroup AF 0.0000401 (3/74876) in African/African American
- threshold for TP53 PM2_Supporting: subgroup AF <0.00004 when multiple alleles are present
Sources
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. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires filtering allele frequency >=0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.064e-05
- TP53 BA1 threshold 0.001
Sources
BS1 This variant does not meet BS1 because the highest observed gnomAD filtering allele frequency is below the TP53 BS1 threshold of 0.0003. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires filtering allele frequency >=0.0003 and <0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.064e-05
- gnomAD v2.1 grpmax FAF 2.138e-05
- TP53 BS1 threshold 0.0003
Sources
BP4 BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate, not BP4, to c.370T>A. BayesDel is 0.257897, which is above the TP53 pathogenic threshold of 0.16, while SpliceAI is 0.02 and does not indicate a splice effect. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires BayesDel below the benign thresholds and no predicted splice effect.
Evidence considered
- PP3-BP4 worksheet row: c.370T>A / p.Cys124Ser
- preliminary code PP3_moderate
- BayesDel 0.257897
- SpliceAI max delta 0.02
- REVEL 0.716
Sources
Not assessed · 7 · no assessment recorded
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. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires the same amino acid change as a previously TP53 VCEP-classified pathogenic or likely pathogenic variant.
Evidence considered
- ClinVar record reviewed
- no qualifying same-amino-acid TP53 VCEP assertion identified in the assembled evidence
Still missing
- A curated same-amino-acid TP53 VCEP comparison would be needed.
Sources
PS2 No confirmed de novo occurrence with the phenotypic detail required for TP53 PS2 scoring was identified. Details ▾Hide ▴
Rule
TP53 VCEP PS2 is point based and requires documented de novo occurrence information.
Evidence considered
- no de novo evidence identified in the reviewed sources
Still missing
- Parental testing and proband cancer-point data were not available.
Sources
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. Details ▾Hide ▴
Rule
TP53 VCEP PM5 is based on prior TP53 VCEP-classified pathogenic or likely pathogenic missense variants at the same residue.
Evidence considered
- no qualifying codon-124 TP53 VCEP pathogenic comparison identified in the reviewed sources
Still missing
- A residue-specific TP53 VCEP pathogenic comparison set would be needed.
Sources
PP1 No segregation data were identified, so there is no evidence to score PP1. Details ▾Hide ▴
Rule
TP53 VCEP PP1 requires 3 or more informative meioses with qualifying Li-Fraumeni syndrome-associated cancers.
Evidence considered
- no segregation evidence identified
Still missing
- Family segregation data with meiosis counts were not available.
Sources
PP4 No case-specific blood variant allele fraction data or constitutional mosaicism observations were identified to support TP53 PP4. Details ▾Hide ▴
Rule
TP53 VCEP PP4 is based on low-VAF observations consistent with constitutional mosaicism in an appropriate clinical context.
Evidence considered
- no PP4-qualifying low-VAF observation data identified
Still missing
- Variant allele fraction and phenotype context were not available.
Sources
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. Details ▾Hide ▴
Rule
TP53 VCEP BS2 requires qualifying unaffected older female carriers from a single source.
Evidence considered
- no BS2-qualifying unaffected carrier data identified
Still missing
- Unaffected-observation data from a single qualifying source were not available.
Sources
BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in affected relatives with qualifying cancers.
Evidence considered
- no BS4 non-segregation evidence identified
Still missing
- Family-level non-segregation evidence was not available.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense change, p.(Cys124Ser), with SpliceAI max delta score 0.02, so it does not meet the TP53 null-variant or splice-disruption framework for PVS1. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 flowchart; PVS1 applies to qualifying null or splice variants, which this variant is not.
Evidence considered
- p.(Cys124Ser) missense consequence
- generic PVS1 scaffold indicates the variant is outside null-variant buckets
- SpliceAI max delta score 0.02
Sources
PM3 N/APM3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM3 as not applicable
Sources
PM4 N/APM4 is not applicable because this variant is a missense substitution and the TP53 VCEP does not use PM4. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM4 as not applicable
Sources
PM6 N/APM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PM6 as not applicable
Sources
PP2 N/APP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP2 as not applicable
Sources
PP5 N/APP5 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks PP5 as not applicable
Sources
BP1 N/ABP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP1 as not applicable
Sources
BP2 N/ABP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP2 as not applicable
Sources
BP3 N/ABP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP3 as not applicable
Sources
BP5 N/ABP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable for TP53 VCEP.
Evidence considered
- TP53 VCEP marks BP5 as not applicable
Sources
BP7 N/ABP7 is a synonymous or intronic rule and is not applicable to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- missense variant p.(Cys124Ser)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.370T>A
- Protein (HGVS p.)
- NP_000537.3:p.(Cys124Ser)
- GRCh38
- chr17:7675999 A>T
- GRCh37
- chr17:7579317 A>T
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.
TP53NM_000546.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,612,186 alleles
AF 1.86e-06 · 0 homozygotes · FAF 1.06e-05
gnomAD v2.1
3 / 282,252 alleles
AF 1.06e-05 · 0 homozygotes · FAF 2.14e-05
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,612,186 alleles · 0 hom · FAF 1.1e-05
| African/African American3 / 74,876 | 4e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 1.1e-05 · 3 / 282,252 alleles · 0 hom · FAF 2.1e-05
| African/African American3 / 24,918 | 0.00012 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ModerateThe 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. Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate for missense variants: Align-GVGD class C65 and BayesDel >=0.16.
Evidence considered
- PP3-BP4 worksheet row: c.370T>A / p.Cys124Ser
- Align-GVGD class C65
- BayesDel 0.257897
- preliminary code PP3_moderate
- SpliceAI max delta 0.02
- REVEL 0.716
Sources
BP4 BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate, not BP4, to c.370T>A. BayesDel is 0.257897, which is above the TP53 pathogenic threshold of 0.16, while SpliceAI is 0.02 and does not indicate a splice effect. Details ▾Hide ▴
Rule
TP53 VCEP BP4 for missense variants requires BayesDel below the benign thresholds and no predicted splice effect.
Evidence considered
- PP3-BP4 worksheet row: c.370T>A / p.Cys124Ser
- preliminary code PP3_moderate
- BayesDel 0.257897
- SpliceAI max delta 0.02
- REVEL 0.716
Sources
BP7 N/ABP7 is a synonymous or intronic rule and is not applicable to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- missense variant p.(Cys124Ser)
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.716. BayesDel score = 0.0594274.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,612,186 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/182926/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579317-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675999-A-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.370T…
- OncoKB ↗www.oncokb.org/gene/TP53/C124S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TP53+c.370T%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.