NM_006231.4:c.4411C>T (p.Arg1471Cys) is a missense variant in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268-471). This variant is present at very low frequency in gnomAD: v2.1 AF=0.00835% (21/251,470 alleles) and v4.1 AF=0.00254% (41/1,614,222 alleles), with zero homozygotes in either dataset (PM2_Supporting).1 The variant is absent from all León-Castillo et al. 2020 supplementary tables (S1, S2, S3) and is not one of the five established pathogenic exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F).2 Computational predictions are mixed: REVEL 0.334 (borderline, below pathogenic threshold of 0.5), BayesDel 0.016 (benign range), SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect per PP3 or a benign effect per BP4.3 Five publications were cited by ClinVar submitters or identified in literature review. Full-text review confirmed none mention NM_006231.4:c.4411C>T or p.Arg1471Cys.4 ClinVar reports this variant as Uncertain significance (VariationID 240513, 7 clinical laboratories, criteria provided single submitter). No expert panel review has been conducted.5 This variant has been reported in COSMIC (COSV57693254, n=5 somatic occurrences), but somatic recurrence does not provide germline pathogenicity evidence. Total evidence: PM2_Supporting (1 supporting pathogenic criterion). No benign criteria met. Classification remains Uncertain Significance.
POLE
Final classification
VUS
POLE c.4411C>T · p.Arg1471Cys
POLE
NM_006231.4:c.4411C>T (p.Arg1471Cys) is a missense variant in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268-471).
Only one supporting-level criterion (PM2_Supporting) was met. The León-Castillo et al. 2020 custom POLE framework does not alter the generic ACMG/AMP 2015 final-category thresholds. Under both the local framework and generic rules, a single supporting criterion is insufficient to reach Likely Pathogenic (minimum: PVS1+1Moderate, 1Strong+1Moderate, 3Moderate, 2Moderate+2Supporting, or 1Moderate+4Supporting) or Likely Benign (minimum: 1StrongBenign+1SupportingBenign or 2SupportingBenign). The evidence falls squarely into the uncertain significance category.
Classification rationale
PM2
VUS
POLE c.4411C>T
PM2
→
VUS
2
vcep_path_250_323_s002vcep_path_250_323_s003vcep_path_250_323_s004
3
revelbayesdelspliceai ↗
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.00835% (21/251,470 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00254% (41/1,614,222 alleles, 0 homozygotes). Highest subpopulation frequency is East Asian at 0.043% (v2.1). Allele frequency is well below the 0.1% threshold for PM2, but the variant is not absent from population databases.
gnomAD v2.1: 21/251470 alleles (AF=0.00835%)v4.1: 41/1
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with the same amino acid change (p.Arg1471Cys) has been identified in ClinVar or the literature.
PS2
No documented de novo occurrence for NM_006231.4:c.4411C>T was identified in the literature or ClinVar submissions.
PS3
No variant-specific functional data or systematic range characterization including position 1471 was identified.
PS4
The León-Castillo et al.
PM1
The León-Castillo et al.
PM5
No same-residue comparator variants with pathogenic or likely pathogenic classification were identified.
PM6
No de novo occurrence of NM_006231.4:c.4411C>T was documented in any reviewed publication or ClinVar submission.
PP1
Although one ClinVar submitter (Invitae SCV000289377) asserted PP1 citing PMIDs 30093976 and 34897210, full-text review of PMID:30093976 confirmed the paper does not mention POLE or this variant.
PP2
POLE is a large gene with considerable benign missense variation in population databases.
PP3
The León-Castillo et al.
PP4
No patient-specific phenotype or clinical information was provided to assess whether the variant explains a highly specific phenotype.
PP5
ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' (7 clinical laboratories).
Benign
BA1
gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both far below the >1% threshold required for BA1.
BS1
gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both below the >0.3% threshold for BS1.
BS2
No homozygous observations in gnomAD (0 homozygotes across v2.1 and v4.1 combined).
BS3
No functional studies demonstrating a neutral effect for this variant or a systematic range including position 1471 were identified in the literature.
BS4
No segregation data is available to assess lack of cosegregation with disease.
BP1
BP1 applies when a missense variant is found in a gene where only truncating variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic POLE variant or in a homozygous state.
BP4
The León-Castillo et al.
BP5
No evidence that variants in POLE cause a disease distinct from the patient's phenotype.
BP6
ClinVar classification is 'Uncertain significance' (7 clinical laboratories).
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.53992e-05; MAF= 0.00254%, 41/1614222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000249858; MAF= 0.02499%, 15/60034 alleles, homozygotes = 0); grpmax FAF= 0.00015347.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.3509e-05; MAF= 0.00835%, 21/251470 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434924; MAF= 0.04349%, 8/18394 alleles, homozygotes = 0); grpmax FAF= 0.00021571.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0025%
· 41 / 1,614,222
0 hom · FAF 0.015%
0 hom · FAF 0.015%
Admixed American 15 / 60,034 |
0.025% |
East Asian 11 / 44,880 |
0.025% |
African/African American 4 / 75,058 |
0.0053% |
South Asian 4 / 91,082 |
0.0044% |
European (non-Finnish) 7 / 1,180,042 |
0.00059% |
+ 5 not observed (Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0084%
· 21 / 251,470
0 hom · FAF 0.022%
0 hom · FAF 0.022%
East Asian 8 / 18,394 |
0.043% |
African/African American 3 / 16,256 |
0.018% |
Admixed American 6 / 34,592 |
0.017% |
Remaining individuals 1 / 6,136 |
0.016% |
South Asian 2 / 30,616 |
0.0065% |
European (non-Finnish) 1 / 113,754 |
0.00088% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
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 (7 clinical laboratories). (ClinVarID = 240513)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = 0.0158517.
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; COSV57693254, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
30093976 ↗
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.
CLINVAR
34897210 ↗
Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.
CLINVAR