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 encodes the leading-strand DNA polymerase that proofreads replication errors, and pathogenic germline variants predispose to polyposis and colorectal cancer. However, p.(Thr41Met) is not a known proofreading-domain hotspot or recurrent cancer variant, and the available evidence - rarity alone offset by a benign in-silico prediction - does not establish whether it alters POLE function. The variant therefore remains of uncertain significance pending functional or segregation data.
Transcript
NM_006231.4
HGVS · transcript:coding
NM_006231.4:c.122C>T
GRCh38
chr12:132681220 G>A
GRCh37
chr12:133257806 G>A
BasisPM2_Moderate (pathogenic) and BP4_Supporting (benign) do not meet any ACMG/AMP 2015 classification combination, so the variant is classified as VUS.▾
PM2_Moderate (pathogenic) and BP4_Supporting (benign) do not meet any ACMG/AMP 2015 classification combination, so the variant is classified as VUS.
Classification rationale
PM2BP4VUS
POLE c.122C>Tmissense · exon 2
PM2 (Moderate): rare in gnomAD v4.1, with an overall allele frequency of 1.98e-05 and no homozygotes. BP4 (Supporting): REVEL 0.177 is below the <0.250 benign-supporting threshold. Final: PM2_Moderate and BP4_Supporting do not combine to meet any ACMG/AMP 2015 threshold, yielding a classification of VUS.
PM2 + BP4→VUS
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLENM_006231.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLE—click a row to locate it on the plot · use the link column to open its page
Variant ↕
Protein
Location
Classification
Link
Applied criteria · 2 applied · 22 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
✓
PM2moderatePathogenic
Met (Moderate): overall allele frequency is 1.98e-05 in gnomAD v4.1, below the 0.1% rarity threshold in every ancestry group.
gnomAD v4.1 reports 32/1,614,120 alleles, overall AF 1.9825e-05, maximum subgroup AF 0.000512409 in East Asian individuals, grpmax FAF 0.0003497, and zero homozygotes.gnomAD v2.1 reports 10/282,864 alleles, overall AF 3.53527e-05, maximum subgroup AF 0.000350842 in East Asian individuals, grpmax FAF 0.00022756, and zero homozygotes.gnomAD-Canada v1.0 reports the variant as absent, providing an additional ancestry/population dataset consistent with rarity.
Met (Supporting): REVEL is 0.177, below the <0.250 benign-supporting threshold.
The governing local POLE framework directs a generic in-silico fallback for exact missense variants absent from Supplementary Table S2 or S3. Direct inspection found no T41M, Thr41Met, c.122C>T, or T41 entry in either table.REVEL is 0.177, below the generic BP4 supporting threshold of <0.250. These REVEL calibration cutoffs are from ClinGen SVI Bayesian calibration work (PMID:36413997).SpliceAI maximum delta is 0.014 and predicts no significant splice impact, but it is not used to adjudicate this missense variant under the generic missense workflow. BayesDel is not used because no verified published threshold is available in this pipeline.
Assessed · not applied
· 7 not met · 15 not assessed
Pathogenic
PS1Not assessed: no pathogenic POLE variant producing the same p.(Thr41Met) change via a different nucleotide change is documented.
PS2Not assessed: no de novo observation is documented; parental testing and trio data are absent.
PS3Not assessed: no validated variant-specific functional assay demonstrating a damaging effect was identified.
PS4Not met: p.(Thr41Met) is not among the four specified variants qualifying for PS4_Supporting under the local POLE rule.
PM1Not met: p.Thr41Met is not one of the specified POLE exonuclease-domain hotspot substitutions.
PM3Not assessed: no proband observations or second allele establish a recessive context for this variant.
PM5Not assessed: no same-residue POLE comparator variants were available, so PM5 semantics could not be confirmed.
PM6Not assessed: no unconfirmed de novo observation is documented.
PP1Not assessed: no segregation data from affected or unaffected relatives are available.
PP2Not assessed: POLE lacks a validated gene-specific rule establishing predominantly pathogenic missense variation.
PP3Not met: REVEL is 0.177, below the >0.750 pathogenic-supporting threshold.
PP4Not assessed: no individual phenotype or clinical diagnosis data are available.
PP5Not met: no ClinVar expert-panel Pathogenic or Likely Pathogenic assertion exists for this exact variant.
Benign
BA1Not met: highest population frequency is 0.00051 (East Asian subgroup), far below the 1% BA1 threshold.
BS1Not met: maximum subgroup frequency is 0.00051 (0.05%), below the 0.3% BS1 threshold.
BS2Not assessed: gnomAD reports zero homozygotes, and no phenotype-ascertained healthy-adult data are available.
BS3Not assessed: no validated functional assay evidence of a normal or benign effect exists for this variant.
BS4Not assessed: no observations of affected relatives lacking the variant are documented.
BP1Not assessed: POLE-related disease is not established as primarily truncating, so the benign-missense rule cannot be applied.
BP2Not assessed: no phase-resolved data show the variant in cis with a pathogenic or in trans with a benign allele.
BP5Not assessed: no individual-level data identify a fully explanatory alternative cause.
BP6Not met: no ClinVar expert-panel Benign or Likely Benign assertion exists for this exact variant.
N/A · 4PVS1 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.9825e-05; MAF= 0.00198%, 32/1614120 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000512409; MAF= 0.05124%, 23/44886 alleles, homozygotes = 0); grpmax FAF= 0.0003497.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.53527e-05; MAF= 0.00354%, 10/282864 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000350842; MAF= 0.03508%, 7/19952 alleles, homozygotes = 0); grpmax FAF= 0.00022756.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.002%
· 32 / 1,614,120
0 hom · FAF 0.035%
East Asian
23 / 44,886
0.051%
Middle Eastern
1 / 6,062
0.016%
African/African American
3 / 75,028
0.004%
European (non-Finnish)
5 / 1,180,008
0.00042%
+ 6 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0035%
· 10 / 282,864
0 hom · FAF 0.023%
East Asian
7 / 19,952
0.035%
African/African American
3 / 24,968
0.012%
+ 6 not observed (Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
Triaged references · 2 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
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
