Starting
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POLE
Final classification
Likely Benign
POLE c.1474-9C>T · p.?
POLE

NM_006231.4:c.1474-9C>T is an intronic substitution in POLE located 9 bases upstream of exon 14. SpliceAI predicts no significant splicing impact (max delta score = 0.01), indicating the variant is unlikely to alter normal splicing.

Gene
POLE
Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.1474-9C>T
Consequence
N/A
GRCh38
chr12:132672848 G>A
GRCh37
chr12:133249434 G>A
Basis The custom León-Castillo et al. 2020 POLE framework was used as the primary classification framework. Only supporting-strength criteria are met: one pathogenic (PM2_Supporting) and two benign (BP4_Supporting, BP6_Supporting). Under the framework's likely_benign combination rules, >=2 Supporting benign criteria are sufficient for a Likely Benign classification.
The custom León-Castillo et al. 2020 POLE framework was used as the primary classification framework. Only supporting-strength criteria are met: one pathogenic (PM2_Supporting) and two benign (BP4_Supporting, BP6_Supporting). Under the framework's likely_benign combination rules, >=2 Supporting benign criteria are sufficient for a Likely Benign classification.
Classification rationale
PM2 BP4BP6 Likely Benign
POLE c.1474-9C>T

NM_006231.4:c.1474-9C>T is an intronic substitution in POLE located 9 bases upstream of exon 14. SpliceAI predicts no significant splicing impact (max delta score = 0.01), indicating the variant is unlikely to alter normal splicing.1 This variant is extremely rare in population databases, with an allele frequency of 4.10e-06 in gnomAD v2.1 (1/244,126 alleles) and 6.20e-07 in gnomAD v4.1 (1/1,611,808 alleles), both meeting the PM2_Supporting threshold for absence from population databases.2 ClinVar classifies this variant as Likely benign (VariationID 2897960, Labcorp Genetics, criteria provided, single submitter), supporting benign interpretation under BP6_Supporting.3 SpliceAI predicts no significant splice impact (max delta score = 0.01), consistent with a neutral computational assessment under BP4_Supporting.4 No pathogenic evidence criteria are met. The custom León-Castillo PM1 and PS4 rules are missense-specific and do not apply to this intronic substitution. The variant is absent from COSMIC and the León-Castillo supplementary tables. No de novo observations, functional studies, or segregation data are available.5 Applying the custom León-Castillo framework with generic ACMG/AMP 2015 fallback: the variant accrues one pathogenic supporting criterion (PM2_Supporting) and two benign supporting criteria (BP4_Supporting, BP6_Supporting). Under the likely_benign combination rules of the framework, two supporting benign criteria are sufficient for a classification of Likely benign. This classification is consistent with the existing ClinVar classification.6

PM2 + BP4 + BP6 Likely Benign
Gene diagram · NM_006231.4 · variants mapped to exon structure
POLE NM_006231.4
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 benign
      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= 6.20421e-07; MAF= 0.00006%, 1/1611808 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23214e-05; MAF= 0.00223%, 1/44800 alleles, homozygotes = 0).
      v2.1
      This variant is present in gnomAD v2.1 (AF= 4.09625e-06; MAF= 0.00041%, 1/244126 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.6035e-05; MAF= 0.00560%, 1/17846 alleles, homozygotes = 0).
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      6.2e-05% · 1 / 1,611,808
      0 hom
      East Asian
      1 / 44,800
      0.0022%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
      gnomAD v2.1
      0.00041% · 1 / 244,126
      0 hom
      East Asian
      1 / 17,846
      0.0056%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 2897960)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      6Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Triaged references · 1 PMID not cited in assessment
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR