About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.370T>C, p.(Cys124Arg)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to p.Cys124Arg. Per VCEP rule: Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays qualifies for PS3 at strong strength. C124R is annotated as Non-functional on Kato data with LOF on Giacomelli and Kotler assays.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%). Absent from all population databases examined.
PP3Moderate
PP3 · moderate
The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.370T>C. Per VCEP rule: aGVGD Class C65 and BayesDel score ≥0.16 qualifies for PP3_moderate. The variant has aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, and SpliceAI max delta 0.02 (no predicted splicing impact).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) = 7 points, which maps to Likely Pathogenic.
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
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
8 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 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.
26 criteria with recorded statuses: 3 met · 6 not met · 6 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
NM_000546.5(NP_000537.3):c.370T>C (p.Cys124Arg) is a missense variant in exon 4 of TP53.
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2_Supporting per TP53 VCEP v2.4.0 (allele frequency <0.003%).
Functional studies demonstrate that p.Cys124Arg is non-functional in the Kato et al. assay and exhibits loss of function in the majority of other eligible assays (Giacomelli, Kotler), meeting PS3 at strong strength per TP53 VCEP specifications (Functional-worksheet.xlsx, Supplementary Table S3).
In silico predictors support a deleterious effect: aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, meeting PP3 at moderate strength per TP53 VCEP specifications (PP3-BP4-codes.xlsx, Supplementary Table S2). SpliceAI predicts no splicing impact (max delta 0.02).
The variant has been reported in ClinVar as Likely pathogenic by one clinical laboratory (ClinVar Variation ID: 4056245) and is observed in COSMIC with 8 somatic occurrences (COSV52752618).
No de novo observations, cosegregation data, proband phenotype scoring, or unaffected elderly carrier data were identified for this variant. PS2, PS4, PP1, PP4, BS2, and BS4 remain unassessed.
Applying the TP53 VCEP v2.4.0 Tavtigian point system: PS3 (+4) + PP3_Moderate (+2) + PM2_Supporting (+1) = +7 points, which falls in the Likely Pathogenic range (6-9 points).
No criteria match.
Met · 3
PS3 StrongThe TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to p.Cys124Arg. Per VCEP rule: Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays qualifies for PS3 at strong strength. C124R is annotated as Non-functional on Kato data with LOF on Giacomelli and Kotler assays. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet.xlsx: C124R assigned PS3 — Non-functional on Kato
- LOF on Giacomelli
- LOF on Kotler
- majority of assays show LOF.
Sources
vcep_functional_worksheet
PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%). Absent from all population databases examined. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1. Absent from gnomAD v4.1. Absent from gnomAD-Canada v1.0.
Sources
PP3 ModerateThe TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.370T>C. Per VCEP rule: aGVGD Class C65 and BayesDel score ≥0.16 qualifies for PP3_moderate. The variant has aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, and SpliceAI max delta 0.02 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- aGVGD Class C65
- BayesDel 0.25469 (≥0.16)
- REVEL 0.883
- SpliceAI max delta 0.02 (no splicing effect). VCEP spreadsheet assigns PP3_moderate.
Sources
Not met · 6 · evaluated, threshold not reached
PM1 Codon 124 is not among the six TP53 VCEP-designated PM1_Moderate codons (175, 245, 248, 249, 273, 282). The alternative PM1 rule requires the variant to be listed on cancerhotspots.org with ≥2 somatic occurrences for PM1_Supporting. The variant is not listed as a statistically significant hotspot on cancerhotspots.org (residue_significant: false, exact_variant_listed: no). Although COSMIC reports 8 somatic occurrences, cancerhotspots.org is the specific database referenced by the VCEP rule. Details ▾Hide ▴
Evidence considered
- Codon 124 not in VCEP PM1_Moderate codons list. cancerhotspots.org: residue not significant
- variant not listed. COSMIC: 8 somatic occurrences but not through cancerhotspots.org.
PM5 PM5 requires a different pathogenic or likely pathogenic missense variant at the same amino acid residue (Cys124) classified per TP53 VCEP specifications. The VCEP Functional-worksheet.xlsx shows other missense variants at codon 124 (C124D: PS3_Supporting; C124G: No evidence; C124S, C124W, C124Y, C124F: BS3), but none have been classified as Pathogenic or Likely Pathogenic by the VCEP. The pm5 candidate search found zero eligible comparator variants. Details ▾Hide ▴
Evidence considered
- Other codon 124 missense variants: C124D (PS3_Supporting — insufficient for P/LP classification)
- C124G (No evidence)
- C124S/W/Y/F (BS3 — benign). No VCEP-classified P/LP comparator at this residue.
Sources
vcep_functional_worksheetpm5_candidates
BA1 The TP53 VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in a non-founder gnomAD continental subpopulation with ≥2,000 alleles and ≥2 alleles present. The variant is absent from gnomAD v2.1 and v4.1. BA1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1. Absent from gnomAD v4.1. Does not meet BA1 threshold of ≥0.1%.
Sources
BS1 The TP53 VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 but <0.001 in a non-founder gnomAD continental subpopulation. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1. Absent from gnomAD v4.1. Does not meet BS1 threshold of ≥0.03%.
Sources
BS3 BS3 requires well-established functional studies showing no deleterious effect. The TP53 VCEP Functional-worksheet.xlsx assigns PS3 (not BS3) to C124R, indicating loss of function across multiple functional assays (Non-functional on Kato, LOF on Giacomelli and Kotler). BS3 is contradicted by the available functional evidence. Details ▾Hide ▴
Evidence considered
- VCEP Functional-worksheet.xlsx: C124R assigned PS3 — loss of function in functional assays. BS3 criteria not met
- as functional evidence demonstrates a deleterious effect.
Sources
vcep_functional_worksheet
BP4 The TP53 VCEP BP4 rule requires BayesDel score <0.16 (Supporting: <0.16 and >-0.008; Moderate: ≤-0.008) AND no predicted splicing impact (SpliceAI <0.2). This variant has BayesDel score 0.25469 (≥0.16), aGVGD Class C65, and REVEL 0.883. These scores are in the pathogenic range and support PP3_moderate, not BP4. BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.25469 (above BP4 threshold of <0.16)
- REVEL 0.883
- aGVGD Class C65. Scores indicate pathogenicity
- not benign impact.
Sources
Not assessed · 6 · no assessment recorded
PS2 No de novo observation with confirmed maternity/paternity was identified for this variant in any reviewed publication or database. The exploratory search suggested the IARC TP53 germline database as a potential source, but no confirmed de novo cases were retrieved. Details ▾Hide ▴
Still missing
- No published de novo cases for NM_000546.5:c.370T>C identified. IARC germline database may contain family history data but was not directly queried.
Sources
911558725741868173923852030148824493721
PS4 PS4 requires a significantly increased prevalence in affected individuals versus controls, scored by proband count and cancer type per the TP53 VCEP PS4 points table. No proband-specific data with cancer phenotypes was identified in the available evidence. The variant is reported in ClinVar (1 submitter, Likely pathogenic) and COSMIC (8 somatic occurrences), but these do not provide the proband-level germline clinical data needed for PS4 scoring. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submitter (Likely pathogenic). COSMIC: 8 somatic occurrences. No proband-level germline phenotype data available.
Still missing
- No germline proband counts with cancer phenotypes available. IARC TP53 germline database may contain proband data for PS4 scoring.
Sources
PP1 No cosegregation data was identified in any reviewed publication. The TP53 VCEP requires 3-4 meioses for PP1_Supporting, 5-6 for PP1_Moderate, and ≥7 for PP1_Strong. No family studies with segregation data for this variant were found. Details ▾Hide ▴
Still missing
- No cosegregation data available. IARC germline database may contain family history information.
Sources
911558725741868173923852030148824493721
PP4 The TP53 VCEP PP4 criterion requires observation of the variant at low variant allele fraction (VAF 5-35%) indicating possible somatic mosaicism or clonal hematopoiesis. No VAF data was available for this variant in the provided evidence. Details ▾Hide ▴
Still missing
- No VAF data available. Clinical laboratory reports or sequencing data may contain VAF information for PP4 assessment.
BS2 The TP53 VCEP BS2 rule requires observation in unrelated females ≥60 years without cancer (≥8 for Strong, 4-7 for Moderate, 2-3 for Supporting). No such data was identified for this variant. Details ▾Hide ▴
Still missing
- No data on unaffected elderly female carriers. Large-scale population or clinical databases may contain this information.
BS4 BS4 requires lack of segregation in affected family members. No segregation data of any kind was identified for this variant. This criterion is typically difficult to assess for rare variants without dedicated family studies. Details ▾Hide ▴
Still missing
- No family segregation studies available. BS4 evidence is typically absent for rare pathogenic variants.
Sources
911558725741868173923852030148824493721
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies to null variants (nonsense, frameshift, canonical splice sites). NM_000546.5:c.370T>C is a missense variant (p.Cys124Arg) and does not fall into any PVS1 null-variant bucket per the TP53 VCEP PVS1 flowchart. Details ▾Hide ▴
Evidence considered
- Missense variant (p.Cys124Arg)
- not a null variant
- no NMD predicted
- not a canonical splice site change.
Sources
pvs1_variant_assessment
PS1 N/APS1 requires a different nucleotide change at the same codon producing the same amino acid change that has been classified as Pathogenic or Likely Pathogenic. p.Cys124Arg is produced by c.370T>C (TGT→CGT). No alternative nucleotide change at codon 124 can produce arginine, as the only Cys codons are TGT/TGC and the only Arg codon reachable via single-nucleotide substitution from these is CGT (via c.370T>C). No alternative nucleotide path exists. Details ▾Hide ▴
Evidence considered
- Codon 124: TGT→CGT is the only single-nucleotide path from cysteine to arginine.
PM6 VCEPPM6 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP5 VCEPBP5 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP6 VCEPBP6 is designated as Not Applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) or intronic variants with no splicing impact. NM_000546.5:c.370T>C is a missense variant (p.Cys124Arg) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous or intronic variants only.
PS5 N/APS5 (PP5 equivalent) is designated as Not Applicable by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.370T>C
- Protein (HGVS p.)
- NP_000537.3:p.(Cys124Arg)
- GRCh38
- chr17:7675999 A>G
- GRCh37
- chr17:7579317 A>G
- ClinVar
- 4056245, 376680
- COSMIC
- COSV52752618
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
- 0.883
- BayesDel
- 0.255
How the predictions were used
PP3 ModerateThe TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.370T>C. Per VCEP rule: aGVGD Class C65 and BayesDel score ≥0.16 qualifies for PP3_moderate. The variant has aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, and SpliceAI max delta 0.02 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- aGVGD Class C65
- BayesDel 0.25469 (≥0.16)
- REVEL 0.883
- SpliceAI max delta 0.02 (no splicing effect). VCEP spreadsheet assigns PP3_moderate.
Sources
BP4 The TP53 VCEP BP4 rule requires BayesDel score <0.16 (Supporting: <0.16 and >-0.008; Moderate: ≤-0.008) AND no predicted splicing impact (SpliceAI <0.2). This variant has BayesDel score 0.25469 (≥0.16), aGVGD Class C65, and REVEL 0.883. These scores are in the pathogenic range and support PP3_moderate, not BP4. BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.25469 (above BP4 threshold of <0.16)
- REVEL 0.883
- aGVGD Class C65. Scores indicate pathogenicity
- not benign impact.
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants with no splicing impact. NM_000546.5:c.370T>C is a missense variant (p.Cys124Arg) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous or intronic variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.883. BayesDel score = 0.25469.
7 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
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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.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
-
PMID 20301488 ↗Li-Fraumeni Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014No paper-specific finding is recorded.
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No 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 0.020
Open source ↗
ClinVar
1 Likely pathogenic
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/4056245/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579317-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675999-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.370T…
- OncoKB ↗www.oncokb.org/gene/TP53/C124R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121501006
- 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 Likely pathogenic (1 clinical laboratory). (ClinVarID = 4056245)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.883. BayesDel score = 0.25469.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.