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TP53
Final classification
VUS
TP53 c.370T>G · p.Cys124Gly
TP53

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).

Gene
TP53
Transcript
NM_000546.5
HGVS · transcript:coding
NM_000546.5:c.370T>G
Consequence
N/A
GRCh38
chr17:7675999 A>C
GRCh37
chr17:7579317 A>C
Basis 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.
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.
Classification rationale
PM2PP3 VUS
TP53 c.370T>G

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).1 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).2 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.3 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.4 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.5 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.6

PM2 + PP3 VUS
2 vcep_pp3_bp4_codesbayesdelspliceai ↗
3 vcep_functional_worksheet
Gene diagram · NM_000546.5 · variants mapped to exon structure
TP53 NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 2 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
      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 Uncertain significance (1 clinical laboratory). (ClinVarID = 230661)
      SpliceAI screenshot
      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 screenshot
      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.
      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; COSV52680549, n = 6 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 · 2 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
      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. CLINVAR