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CTNNA1
Final classification
VUS
CTNNA1 c.1618C>T · p.Arg540Cys
CTNNA1

The CTNNA1 c.1618C>T (p.Arg540Cys) variant has been reported in ClinVar, where it is currently classified as uncertain significance by 4 clinical laboratories without expert panel review.

Gene
CTNNA1
Transcript
NM_001903.5
HGVS · transcript:coding
NM_001903.5:c.1618C>T
Consequence
N/A
GRCh38
chr5:138924581 C>T
GRCh37
chr5:138260270 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2 VUS
CTNNA1 c.1618C>T

The CTNNA1 c.1618C>T (p.Arg540Cys) variant has been reported in ClinVar, where it is currently classified as uncertain significance by 4 clinical laboratories without expert panel review.1 This variant is rare in population databases, with gnomAD v2.1 showing 1/251442 alleles (0.00040%) and gnomAD v4.1 showing 11/1613994 alleles (0.00068%), both below the 0.1% PM2 threshold and with no homozygotes observed.2 No variant-specific well-established functional study was identified for p.Arg540Cys in the retrieved materials.3 In silico evidence is not concordant enough to support either PP3 or BP4: SpliceAI predicts no splice impact (max delta score 0.00), while REVEL is 0.305 and BayesDel is 0.105968.4

PM2 → VUS
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 oncokb ↗PMID:32051609 ↗
4 spliceai ↗revelbayesdel
Gene diagram · NM_001903.5 · variants mapped to exon structure
CTNNA1 NM_001903.5
Fetching transcript structure from UCSC…
Applied criteria · 1 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
      This variant is present in gnomAD v4.1 (AF= 6.81539e-06; MAF= 0.00068%, 11/1613994 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.00117e-05; MAF= 0.00500%, 3/59986 alleles, homozygotes = 0); grpmax FAF= 1.327e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 3.97706e-06; MAF= 0.00040%, 1/251442 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89184e-05; MAF= 0.00289%, 1/34580 alleles, homozygotes = 0).
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00068% · 11 / 1,613,994
      0 hom · FAF 0.0013%
      Admixed American
      3 / 59,986
      0.005%
      European (non-Finnish)
      8 / 1,180,052
      0.00068%
      + 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0004% · 1 / 251,442
      0 hom
      Admixed American
      1 / 34,580
      0.0029%
      + 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 661855)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.305. BayesDel score = 0.105968.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNA1, a cytoplasmic adhesion protein, is infrequently altered 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; COSV100242785, n = 4 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 4 PMIDs not cited in assessment
      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
      32051609 ↗ Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer. CLINVAR
      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
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR