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POLE
Final classification
VUS
PM2BP4
POLE
c.1794+19G>T
p.?
unknown · exon 16i
Gene context NCBI Gene ↗ OncoKB ↗

POLE encodes the catalytic subunit of DNA polymerase epsilon, the enzyme that replicates the leading strand of DNA during cell division and participates in DNA repair. It contains a proofreading domain that corrects replication errors, keeping the accumulation of mutations in check. Germline mutations in POLE cause polyposis and predispose to colorectal cancer, and are also linked to a rare syndrome of facial dysmorphism, immunodeficiency, livedo, and short stature. Somatic mutations, particularly in the proofreading domain, occur in colorectal and endometrial cancers, where they drive an ultra-mutated tumor phenotype and are associated with better responses to immune checkpoint inhibitors.

This variant

POLE's main disease mechanism is missense change in its proofreading domain, so a deep intronic substitution falls outside the recognized pathogenic pattern. With no predicted splice effect (SpliceAI max delta 0.031) yet essentially no population frequency (2/1,568,238 alleles), current evidence cannot determine whether this variant alters POLE function or colorectal cancer predisposition, hence VUS.

Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.1794+19G>T
GRCh38
chr12:132672196 C>A
GRCh37
chr12:133248782 C>A
Basis Only PM2 (Supporting) and BP4 (Supporting) are met, which does not satisfy any pathogenic or benign ACMG/AMP combination, so the classification is VUS. ▾
Only PM2 (Supporting) and BP4 (Supporting) are met, which does not satisfy any pathogenic or benign ACMG/AMP combination, so the classification is VUS.
Classification rationale
PM2 BP4 VUS
POLE c.1794+19G>T unknown · exon 16i

PM2 (Supporting): essentially absent from population databases - only 2/1,568,238 alleles in gnomAD v4.1 and none in gnomAD v2.1 or gnomAD-Canada v1.0, below the 0.1% rare-variant threshold. BP4 (Supporting): SpliceAI max delta 0.031 is below the <0.1 threshold, predicting no significant splice impact. Synthesis: with only PM2_Supporting and BP4_Supporting, no pathogenic or benign ACMG/AMP 2015 combination is reached, yielding a classification of VUS.

PM2 + BP4 → VUS
Gene diagram · NM_006231.4 · variants mapped to exon structure
POLE NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with only 2/1,568,238 alleles (AF 1.28e-06) in gnomAD v4.1, below the 0.1% rare-variant threshold.
The variant is absent from gnomAD v2.1.gnomAD v4.1 reports 2/1,568,238 total alleles, total AF 1.27532e-06, 0 homozygotes, and maximum reported subpopulation AF 3.28267e-05 from 2/60,926 alleles.The variant is absent from gnomAD-Canada v1.0.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (Supporting): SpliceAI max delta 0.031 is below the <0.1 BP4 threshold, predicting no significant splice impact.
The local POLE BP4 rule applies only to exact missense variants represented in Supplementary Table S2 or S3. The queried c.1794+19G>T intronic variant is absent from both reviewed tables, so the generic non-missense pathway applies.SpliceAI reports a maximum delta of 0.031 (DS_DG 0.031), below the generic BP4 threshold of 0.1 for intronic, synonymous, or non-canonical splice-position variants.
spliceai ↗
Assessed · not applied · 6 not met · 12 not assessed
Pathogenic
PVS1 Not met: deep intronic substitution with no defined protein consequence (p.?) and SpliceAI max delta 0.031, predicting no loss-of-function splice alteration.
PS2 Not assessed: no parental testing results establish that the variant is absent from both biological parents (de novo).
PS3 Not assessed: no validated functional assay evidence for this variant was available to demonstrate a damaging effect.
PS4 Not assessed: the POLE framework's PS4 applies only to recurrent missense hotspots, and no case-control enrichment data exist for this intronic variant.
PM3 Not assessed: no affected-proband observations, pathogenic allele in the same gene, or phase data establish a trans configuration.
PM6 Not assessed: no parental testing or phenotype concordance data support a de novo occurrence.
PP1 Not assessed: no pedigree or segregation data from affected or unaffected relatives were available.
PP3 Not met: SpliceAI max delta 0.031 is below the >0.2 PP3 threshold, predicting no splice impact.
PP4 Not assessed: no individual or tumor phenotype data establish a presentation highly specific to POLE-related disease.
PP5 Not met: the ClinVar record has no expert-panel submission, only a single clinical laboratory assertion.
Benign
BA1 Not met: the highest allele frequency (3.28e-05) is far below the 1% BA1 threshold.
BS1 Not met: the highest allele frequency (3.28e-05) is below the 0.3% BS1 threshold.
BS2 Not assessed: no evidence documents carriers as phenotypically healthy adults, so benign homozygosity cannot be established.
BS3 Not assessed: no functional assay evidence demonstrated a benign effect; the single-submitter Likely benign ClinVar entry is not functional evidence.
BS4 Not assessed: no unaffected-carrier relatives or non-segregating meioses were documented.
BP2 Not assessed: no co-occurrence of the variant with a pathogenic allele or cis/trans phase data were available.
BP5 Not assessed: no carrier genotype or phenotype data show the phenotype is explained by an alternative molecular diagnosis.
BP6 Not met: the single Likely benign laboratory submission cannot trigger BP6 because the record has no expert-panel submission.
N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
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= 1.27532e-06; MAF= 0.00013%, 2/1568238 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.28267e-05; MAF= 0.00328%, 2/60926 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013% · 2 / 1,568,238
0 hom
Remaining individuals
2 / 60,926
0.0033%
+ 9 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 2900761)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
SpliceAI ↗
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
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 1 PMID not cited in assessment
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR