NM_006231.3:c.4735C>T (p.Arg1579Cys) is a missense variant in the C-terminal polymerase domain of POLE, distant from the exonuclease domain (residues 1-466) where established pathogenic missense variants cluster.1 This variant is present at very low frequency in population databases: gnomAD v2.1 at 0.00319% (1/31,386 alleles), gnomAD v4.1 at 0.00050% (8/1,613,270 alleles), and absent from gnomAD-Canada, meeting PM2 at supporting strength.2 Under the León-Castillo et al. 2020 custom POLE framework, this variant does not qualify for PM1 (not an exonuclease-domain hotspot), PS4 (not a recurrent pathogenic variant in endometrial carcinoma cohorts), PP3 (absent from supplementary in silico tables), or BP4 (absent from supplementary in silico tables).3 Computational predictors are mixed and do not converge on a pathogenic signal: REVEL 0.412 (intermediate), BayesDel 0.071 (benign-leaning), SpliceAI max delta 0.20 (borderline). PP3 and BP4 are not met.4 This variant is reported in ClinVar (VariationID 405672) as 'Uncertain significance' by three clinical laboratories. The associated publications (PMID:25394175, a cancer genetics referral guideline, and PMID:28492532, the Sherloc classification framework) do not provide variant-specific evidence for NM_006231.3:c.4735C>T.5 No functional studies, segregation data, de novo observations, or case-control studies are available for this variant. All remaining pathogenic criteria (PS1-PS5, PM1, PM5-PM6, PP1-PP5) and benign criteria (BA1, BS1-BS4, BP1-BP6) are either not met or not applicable.6 With only PM2_Supporting met, the overall classification is Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines: insufficient evidence to classify as pathogenic or benign.7
POLE
Final classification
VUS
PM2
POLE
c.4735C>T
p.Arg1579Cys
This variant
NM_006231.3:c.4735C>T (p.Arg1579Cys) is a missense variant in the C-terminal polymerase domain of POLE, distant from the exonuclease domain (residues 1-466) where established pathogenic missense variants cluster.
Only PM2 is met at supporting strength. No PVS1, no Strong (PS), no additional Moderate (PM), and no other Supporting pathogenic criteria are met. No benign criteria are met. Under both the León-Castillo et al. 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules, a single supporting criterion is insufficient to classify as Pathogenic, Likely Pathogenic, Benign, or Likely Benign. The variant defaults to VUS.
Classification rationale
PM2
VUS
POLE c.4735C>T
PM2
→
VUS
1
vcep_path_250_323pvs1_variant_assessment
3
vcep_path_250_323_s002vcep_path_250_323_s003vcep_path_250_323_s004final_classification_framework
4
revelbayesdelspliceai ↗
6
oncokb ↗pm5_candidates
7
generic_acmg_combination_rules
Gene diagram
· NM_006231.3 · variants mapped to exon structure
POLE
NM_006231.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases, meeting PM2 at supporting strength. gnomAD v2.1 AF = 0.00319% (1/31,386 alleles), gnomAD v4.1 AF = 0.00050% (8/1,613,270 alleles, grpmax FAF = 2.92e-06), and the variant is absent from gnomAD-Canada. All frequencies are well below the 0.1% threshold. No homozygotes have been observed in any population database.
gnomAD v2.1: 1/31386 alleles (0.00319%)0 homozygotes
Assessed · not applied
· 20 not met · 1 not assessed
Pathogenic
PS1
No known pathogenic variant at the same amino acid position (Arg1579) with the same nucleotide change has been identified in ClinVar or the literature.
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies demonstrating a damaging effect have been identified for this variant.
PS4
Under the León-Castillo et al.
PM1
Under the León-Castillo et al.
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP2
PP2 requires demonstration that the gene has a low rate of benign missense variation (high missense Z-score) and that missense variants are a common disease mechanism.
PP3
Under the León-Castillo et al.
PP4
No specific patient phenotype or clinical information is available for this variant to assess whether the phenotype is highly specific for POLE-related disease.
PP5
This variant is reported in ClinVar (VariationID 405672) as 'Uncertain significance' by three clinical laboratories with review status 'criteria provided, single submitter.' The ClinVar-associated PMIDs do not provide variant-specific evidence: PMID 25394175 (Hampel et al.
Benign
BA1
Variant frequency in population databases is well below the 1% threshold for BA1.
BS1
Variant frequency is well below the 0.3% threshold for BS1.
BS2
No evidence of this variant being observed in a healthy adult individual for a fully penetrant disorder.
BS3
No well-established functional studies showing no damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
No evidence of this variant being observed in trans with a known pathogenic POLE variant.
BP4
Under the León-Castillo et al.
BP5
No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.95887e-06; MAF= 0.00050%, 8/1613270 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.78165e-06; MAF= 0.00068%, 8/1179654 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18613e-05; MAF= 0.00319%, 1/31386 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48593e-05; MAF= 0.00649%, 1/15418 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,613,270
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
European (non-Finnish) 8 / 1,179,654 |
0.00068% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0032%
· 1 / 31,386
0 hom
0 hom
European (non-Finnish) 1 / 15,418 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 405672)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.412. BayesDel score = 0.0712825.
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. 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
COSMIC
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; COSV57690476, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
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