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TP53
Final classification
VUS
TP53 c.413C>A · p.Ala138Asp
TP53

c.413C>A (p.Ala138Asp) in TP53 is a missense variant in exon 5. It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

Gene
TP53
Transcript
NM_000546.5
HGVS · transcript:coding
NM_000546.5:c.413C>A
Consequence
N/A
GRCh38
chr17:7675199 G>T
GRCh37
chr17:7578517 G>T
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.413C>A

c.413C>A (p.Ala138Asp) in TP53 is a missense variant in exon 5. It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).1 In silico predictions are consistent with a deleterious effect: aGVGD Class C65, BayesDel 0.540498, REVEL 0.901, and SpliceAI predicts no splicing impact (max delta 0.01). The TP53 VCEP assigns PP3_moderate.2 Functional data from the TP53 VCEP Functional-worksheet (Supplementary Table S3) assign 'No evidence' to p.Ala138Asp: Kato shows partially functional, Funk shows LOF, but Giacomelli and Kotler show noLOF. Neither PS3 nor BS3 criteria are met.3 The variant is not located in a VCEP-specified PM1 hotspot codon (175, 245, 248, 249, 273, 282), and the exact variant is not listed in cancerhotspots.org (PM1 not met). This variant has been reported in ClinVar as Uncertain Significance by the ClinGen TP53 Variant Curation Expert Panel (ClinVar ID: 528270) and has been observed 3 times in somatic cancers (COSMIC COSV53502932).4 PVS1, PS5, PM6, PP2, PP5, BP1, BP2, BP5, BP6, and BP7 are not applicable per the TP53 VCEP v2.4.0 specifications or by variant type. PS1, PS2, PS4, PM5, PP1, PP4, BS2, BS4, and BS5 remain not assessed due to insufficient clinical data.5

PM2 + PP3 VUS
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 (2 clinical laboratories) and as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 528270)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.901. BayesDel score = 0.540498.
      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 Hotspot
      COSMIC
      This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53502932, n = 3 times).
      Hotspots
      This variant lies 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 · 9 PMIDs not cited in assessment
      11900253 ↗ Rescuing the function of mutant p53. ONCOKB
      8023157 ↗ Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. ONCOKB
      12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. CLINVAR
      29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. CLINVAR
      30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer. CLINVAR
      9472631 ↗ Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene. CLINVAR
      17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
      20301488 ↗ Li-Fraumeni Syndrome. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR