Starting
Initialising…
0%
TP53
Final classification
Likely Pathogenic
TP53 c.370T>C · p.Cys124Arg
TP53

NM_000546.5(NP_000537.3):c.370T>C (p.Cys124Arg) is a missense variant in exon 4 of TP53.

Gene
TP53
Transcript
NM_000546.5
HGVS · transcript:coding
NM_000546.5:c.370T>C
Consequence
N/A
GRCh38
chr17:7675999 A>G
GRCh37
chr17:7579317 A>G
Basis 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.
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.
Classification rationale
PS3PM2PP3 Likely Pathogenic
TP53 c.370T>C

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%).1 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).2 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).3 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).4 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).5

PS3 + PM2 + PP3 Likely Pathogenic
2 vcep_functional_worksheet
3 vcep_pp3_bp4_codesbayesdelrevelspliceai ↗
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 pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 4056245)
      SpliceAI screenshot
      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 screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 7 PMIDs not cited in assessment
      9115587 ↗ Reappraisal of p53 mutations in human malignant astrocytic neoplasms by p53 functional assay: comparison with conventional structural analyses. ONCOKB
      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. CLINVAR
      17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
      20301488 ↗ Li-Fraumeni Syndrome. CLINVAR
      24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
      26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR
      26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR