About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.370T>G, p.(Cys124Gly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold (allele frequency < 0.003% / 0.00003 in large population databases).
PP3Moderate
PP3 · moderate
The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns c.370T>G a pre-computed code of PP3_moderate based on aGVGD Class C65 and BayesDel score 0.216879 (≥0.16). SpliceAI max delta score is 0.04, indicating no predicted splicing effect, so in silico evidence is not confounded by splicing.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + PP3 moderate (+2) = 3 points, which maps to VUS.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52680549, n = 6 times).
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.
29 criteria with recorded statuses: 2 met · 12 not met · 1 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000546.5:c.370T>G (p.Cys124Gly) is a missense variant in TP53 exon 4, absent from gnomAD v2.1 and v4.1 (PM2_Supporting met; 1 point).
In silico analysis per TP53 VCEP assigns PP3_Moderate: aGVGD Class C65 and BayesDel 0.217 (≥0.16), with no predicted splicing effect (SpliceAI max delta 0.04) (2 points).
No functional evidence is applicable per the TP53 VCEP Functional-worksheet, which assigns C124G a code of 'No evidence' due to mixed assay results: Kato partially functional, Giacomelli LOF, Kotler noLOF.
The variant has been observed 6 times in somatic cancers (COSMIC COSV52680549) but is not listed in cancerhotspots.org as a statistically significant hotspot, and codon 124 is not among the VCEP-defined PM1 hotspot codons.
No proband-level phenotype, cosegregation, de novo, or case-control data are available for this variant. ClinVar reports a single submitter classification of Uncertain significance.
Total Tavtigian points: PM2_Supporting (1) + PP3_Moderate (2) = 3 points, falling within the TP53 VCEP VUS range (-1 to 5 points). The variant is classified as Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold (allele frequency < 0.003% / 0.00003 in large population databases). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- Absent from gnomAD v4.1 (0 alleles).
Sources
PP3 ModerateThe TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns c.370T>G a pre-computed code of PP3_moderate based on aGVGD Class C65 and BayesDel score 0.216879 (≥0.16). SpliceAI max delta score is 0.04, indicating no predicted splicing effect, so in silico evidence is not confounded by splicing. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.370T>G → PP3_moderate
- aGVGD: Class C65
- BayesDel: 0.216879 (≥0.16 meets PP3 threshold)
- SpliceAI max delta: 0.04 (no predicted splicing impact)
- REVEL: 0.843
Sources
Not met · 12 · evaluated, threshold not reached
PS2 No confirmed de novo occurrence of NM_000546.5:c.370T>G with confirmed paternity/maternity has been identified in published literature or databases. Details ▾Hide ▴
Evidence considered
- Exploratory literature search did not identify any de novo reports for this variant.
Still missing
- No published de novo case with confirmed parentage was found.
PS3 The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns C124G a code of 'No evidence.' The Kato assay showed partially functional activity; Giacomelli showed LOF but Kotler showed noLOF. The mixed results do not meet any PS3 strength threshold: PS3_Strong requires non-functional on Kato + LOF by majority of other assays; PS3_Moderate requires partially functional on Kato + LOF by majority of other assays (only 1 of 2 other assays shows LOF); PS3_Supporting requires non-functional on Kato (C124G is partially functional). Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet: C124G → 'No evidence'
- Kato: Partially functional
- Giacomelli: LOF
- Kotler: noLOF
- Kawaguchi: NA
Sources
vcep_functional_worksheet
PS4 No proband data meeting the TP53 VCEP PS4 point system (LFS-associated cancers per proband) is available for this variant. The variant is observed 6 times in COSMIC (somatic) but no germline case-control or prevalence data were identified. The single ClinVar submission classifies the variant as Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submission
- Uncertain significance
- COSMIC: 6 somatic observations (COSV52680549)
- No germline case-control or proband data identified.
Still missing
- No proband-level LFS cancer phenotype data available for PS4 scoring.
Sources
PM1 Codon 124 is not among the TP53 VCEP-defined mutational hotspot codons (175, 245, 248, 249, 273, 282) for PM1_Moderate. The variant is not listed in cancerhotspots.org as a statistically significant hotspot, so neither PM1_Supporting (2-9 somatic occurrences per cancerhotspots.org) applies. Details ▾Hide ▴
Evidence considered
- VCEP PM1 hotspot codons: 175
- 245
- 248
- 249
- 273
- 282. Codon 124 is not in this list.
- cancerhotspots.org: variant not found in significant hotspots.
- COSMIC: 6 somatic observations but not via cancerhotspots.org.
Sources
PP1 No published cosegregation data for NM_000546.5:c.370T>G in affected family members has been identified. TP53 VCEP PP1 requires observed cosegregation in ≥3 meioses for Supporting, 5-6 for Moderate, or ≥7 for Strong. Details ▾Hide ▴
Evidence considered
- No cosegregation studies identified for this variant in published literature.
Still missing
- No family cosegregation data available.
PP4 No proband-specific phenotype data or variant allele fraction (VAF) observations meeting the TP53 VCEP PP4 thresholds are available. PP4 requires variant observation with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate). Details ▾Hide ▴
Evidence considered
- No proband-level VAF or phenotype data identified for this variant.
Still missing
- No proband phenotype or VAF data available.
BA1 The variant is absent from gnomAD v2.1 and v4.1, so the TP53 VCEP BA1 threshold (filtering allele frequency ≥0.001 / 0.1% in a single continental genetic ancestry group) is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (allele frequency = 0).
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1, so the TP53 VCEP BS1 threshold (filtering allele frequency ≥0.0003 but <0.001 in a single continental genetic ancestry group) is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (allele frequency = 0).
Sources
BS2 No data are available regarding unrelated females ≥60 years of age without cancer carrying this variant. BS2 requires ≥2 such individuals for Supporting, 4-7 for Moderate, or ≥8 for Strong, all from a single source. Details ▾Hide ▴
Evidence considered
- No healthy elderly female carriers identified.
Still missing
- No data on healthy older adult carriers.
BS3 The TP53 VCEP Functional-worksheet assigns C124G a code of 'No evidence.' The Kato assay showed partially functional (not 'Functional') activity, so neither BS3_Strong (requires Functional on Kato + no LOF by majority) nor BS3_Supporting (requires Partially functional on Kato + no LOF by all assays; Giacomelli shows LOF) is met. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet: C124G → 'No evidence'
- Kato: Partially functional
- Giacomelli: LOF
- Kotler: noLOF
Sources
vcep_functional_worksheet
BS4 No reports of non-segregation (apparently healthy individuals carrying the variant in affected families) for c.370T>G have been identified. BS4 requires lack of segregation in affected family members with LFS-associated cancers. Details ▾Hide ▴
Evidence considered
- No non-segregation data identified.
Still missing
- No family non-segregation data available.
BP4 The TP53 VCEP PP3-BP4-codes spreadsheet assigns c.370T>G a code of PP3_moderate, not BP4. The variant has aGVGD Class C65 (most pathogenic class) and BayesDel 0.216879 (≥0.16), which are incompatible with BP4 application. BP4_Moderate requires BayesDel ≤ -0.008; BP4_Supporting requires BayesDel <0.16 and > -0.008. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.370T>G → PP3_moderate (not BP4)
- aGVGD: Class C65 (Blocks BP4 per VCEP flowchart)
- BayesDel: 0.216879 (≥0.16
- incompatible with BP4)
Sources
vcep_pp3_bp4_codesbayesdel
Not assessed · 1 · no assessment recorded
PM5 Other missense variants exist at codon 124 (e.g., C124R, C124S) but none have been definitively classified as Pathogenic or Likely Pathogenic following TP53 VCEP specifications. The PM5 candidates pipeline returned a false-negative 'not_applicable' recommendation (misclassifying this clearly missense variant as non-missense). Manual review of comparators is needed to determine if any qualify under VCEP PM5 rules (PM5_Strong: ≥2 different pathogenic missense at same residue; PM5_Moderate: 1 pathogenic; PM5_Supporting: 1 likely pathogenic with clinical data). Details ▾Hide ▴
Evidence considered
- Codon 124 has other missense variants (C124R
- C124S
- C124F
- C124Y
- etc.) in the VCEP functional worksheet but none with final VCEP P/LP classification confirmed.
Still missing
- Need VCEP final classification for comparator missense variants at codon 124 (e.g.
- C124R which has PS3 functional evidence).
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants; it is reserved for null variants (nonsense, frameshift, canonical splice sites, initiation codon, and CNVs) per the TP53 VCEP PVS1 flowchart. This variant (NM_000546.5:c.370T>G) is a missense substitution producing p.Cys124Gly. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant.
- TP53 VCEP PVS1 flowchart applies only to null variants.
PS1 N/APS1 requires a different nucleotide change at the same codon that produces the same amino acid change and has been classified as Pathogenic per TP53 VCEP specifications. The only nucleotide change producing p.Cys124Gly is c.370T>G itself; no alternative nucleotide change yielding C124G with a prior pathogenic classification was identified. Details ▾Hide ▴
Evidence considered
- Codon TGC → GGC produces C124G uniquely via c.370T>G
- no alternative synonymous nucleotide change exists that could serve as a PS1 comparator.
PM3 VCEPTP53 is associated with autosomal dominant disease; PM3 (detected in trans with a pathogenic variant) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPVariant is a missense substitution, not a protein-length changing variant (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is marked as Not Applicable by the TP53 VCEP v2.4.0. No de novo data are available for this variant, but the criterion itself is not in use per VCEP specifications. Details ▾Hide ▴
PP2 VCEPPP2 is marked as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly marked as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee (TP53 VCEP v2.4.0). Details ▾Hide ▴
BP1 VCEPBP1 is marked as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP2 VCEPBP2 is marked as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP3 VCEPVariant is a substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPBP5 is marked as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP6 VCEPBP6 is marked as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants per the TP53 VCEP PP3/BP4/BP7 flowchart. NM_000546.5:c.370T>G is a missense variant producing p.Cys124Gly and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous or intronic.
PS5 N/APS5 is not a criterion defined or used by the TP53 VCEP v2.4.0. The analogous PP5 criterion is explicitly marked as Not Applicable for this VCEP per ClinGen SVI guidance. Details ▾Hide ▴
Evidence considered
- TP53 VCEP v2.4.0 does not define PS5
- PP5 is Not Applicable per VCEP.
Sources
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.370T>G
- Protein (HGVS p.)
- NP_000537.3:p.(Cys124Gly)
- GRCh38
- chr17:7675999 A>C
- GRCh37
- chr17:7579317 A>C
- ClinVar
- 230661, 187052
- COSMIC
- COSV52680549
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.843
- BayesDel
- 0.217
How the predictions were used
PP3 ModerateThe TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns c.370T>G a pre-computed code of PP3_moderate based on aGVGD Class C65 and BayesDel score 0.216879 (≥0.16). SpliceAI max delta score is 0.04, indicating no predicted splicing effect, so in silico evidence is not confounded by splicing. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.370T>G → PP3_moderate
- aGVGD: Class C65
- BayesDel: 0.216879 (≥0.16 meets PP3 threshold)
- SpliceAI max delta: 0.04 (no predicted splicing impact)
- REVEL: 0.843
Sources
BP4 The TP53 VCEP PP3-BP4-codes spreadsheet assigns c.370T>G a code of PP3_moderate, not BP4. The variant has aGVGD Class C65 (most pathogenic class) and BayesDel 0.216879 (≥0.16), which are incompatible with BP4 application. BP4_Moderate requires BayesDel ≤ -0.008; BP4_Supporting requires BayesDel <0.16 and > -0.008. Details ▾Hide ▴
Evidence considered
- VCEP PP3-BP4-codes: c.370T>G → PP3_moderate (not BP4)
- aGVGD: Class C65 (Blocks BP4 per VCEP flowchart)
- BayesDel: 0.216879 (≥0.16
- incompatible with BP4)
Sources
vcep_pp3_bp4_codesbayesdel
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants per the TP53 VCEP PP3/BP4/BP7 flowchart. NM_000546.5:c.370T>G is a missense variant producing p.Cys124Gly and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous or intronic.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.843. BayesDel score = 0.216879.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 9115587 ↗Reappraisal of p53 mutations in human malignant astrocytic neoplasms by p53 functional assay: comparison with conventional structural analyses.No paper-specific finding is recorded.
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
1 Uncertain significance
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/230661/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579317-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675999-A-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.370T…
- OncoKB ↗www.oncokb.org/gene/TP53/C124G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121589410
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 230661)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.843. BayesDel score = 0.216879.
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 previously been reported in somatic cancers (COSMIC; COSV52680549, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.