About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.4735C>T, p.(Arg1579Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is León-Castillo et al. 2020 custom POLE framework. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,613,270 alleles
gnomAD v4.1: 8 / 1,613,270 alleles. Recorded AF 4.95887e-06. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.200 maximum delta
Recorded SpliceAI maximum delta score: 0.200. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57690476, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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).
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.
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.
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.
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.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/31
- 386 alleles (0.00319%)
- 0 homozygotes
- gnomAD v4.1: 8/1
- 613
- 270 alleles (0.00050%)
- absent from gnomAD-Canada.
Sources
Not met · 21 · evaluated, threshold not reached
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. Details ▾Hide ▴
Evidence considered
- ClinVar variation 405672 is classified as VUS (not pathogenic)
- PM5 candidate search found zero same-residue comparator variants.
Sources
clinvar ↗pm5_candidates
PS2 No de novo data are available for this variant. No publications report de novo occurrence of NM_006231.3:c.4735C>T. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified in ClinVar submissions or the literature.
Still missing
- No trio or de novo studies available for this variant.
PS3 No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' No publications with variant-specific functional data were found. Details ▾Hide ▴
Evidence considered
- OncoKB reports no reviewed functional evidence for R1579C
- no publications with variant-specific functional assays identified.
Still missing
- No functional studies available for this variant.
Sources
PS4 Under the León-Castillo et al. 2020 custom POLE framework, PS4_Supporting applies only to four specific hotspot variants (P286R, V411L, A456P, S297F) with combined endometrial carcinoma count ≥10 in Supplementary Table S1. R1579C is not among these variants and is absent from Table S1. Under generic ACMG, no case-control studies demonstrating statistically significant enrichment in affected individuals are available. The variant has been observed in COSMIC (n=2) but this somatic recurrence is insufficient for germline PS4. Details ▾Hide ▴
Evidence considered
- Variant is absent from Supplementary Table S1 (recurrent POLE variants in EC)
- COSMIC reports two somatic occurrences
- no germline case-control data available.
Still missing
- No case-control studies for this variant.
Sources
vcep_path_250_323_s002clinvar ↗
PM1 Under the León-Castillo et al. 2020 custom POLE framework, PM1 applies only to specific exonuclease-domain hotspot variants listed in Supplementary Table S1. R1579C is at residue 1579, far outside the POLE exonuclease domain (residues ~1-466), and is not among the specified variants at any strength tier (Strong: P286R/V411L/S297F/A456P/S459F; Moderate: F367S/L424I/M295R/P436R/M444K/D368Y; Supporting: A465V/L424V/T278M/A428T). The variant is absent from Supplementary Table S1. Under generic ACMG, this residue is not located in a well-established mutational hotspot or critical functional domain. Details ▾Hide ▴
Evidence considered
- Residue 1579 is in the C-terminal polymerase domain
- far from the exonuclease domain (1-466)
- variant absent from León-Castillo Table S1
- not in any established POLE hotspot.
Sources
vcep_path_250_323vcep_path_250_323_s002final_classification_framework
PM6 No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or the literature.
Still missing
- No trio or de novo testing data available.
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No segregation data available.
PP3 Under the León-Castillo et al. 2020 custom POLE framework, PP3_Supporting requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and benign in silico results ≤1. R1579C is absent from both tables. Under generic ACMG, the computational evidence is mixed and does not support a deleterious effect: REVEL score is 0.412 (intermediate, below typical pathogenic threshold of 0.5), BayesDel score is 0.071 (benign-leaning), and SpliceAI max delta is 0.20 (borderline). Multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.412 (intermediate)
- BayesDel 0.071 (benign-leaning)
- SpliceAI max delta 0.20 (borderline)
- variant absent from León-Castillo Tables S2 and S3.
Sources
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. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for individuals carrying this variant.
Still missing
- No patient phenotype data available.
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. 2015) is a general cancer genetics referral guideline that does not mention NM_006231.3:c.4735C>T; PMID 28492532 (Nykamp et al. 2017, Sherloc) describes a variant classification framework and does not contain variant-specific evidence. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS (3 submitters)
- associated PMIDs are general guidelines/frameworks
- not variant-specific evidence.
Sources
BA1 Variant frequency in population databases is well below the 1% threshold for BA1. Maximum observed frequency is 0.00649% in gnomAD v2.1 European (non-Finnish) and 0.00050% overall in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF = 0.00649% (NFE)
- gnomAD v4.1 overall AF = 0.00050%
- both far below 1% BA1 threshold.
Sources
BS1 Variant frequency is well below the 0.3% threshold for BS1. Maximum population frequency is 0.00649% in gnomAD v2.1 European (non-Finnish). Details ▾Hide ▴
Evidence considered
- Max population AF = 0.00649%
- far below the 0.3% BS1 threshold.
Sources
BS2 No evidence of this variant being observed in a healthy adult individual for a fully penetrant disorder. No homozygous observations in population databases. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data or homozygous occurrences.
Still missing
- No data on healthy adult carriers.
BS3 No well-established functional studies showing no damaging effect on protein function or splicing have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies (benign or pathogenic) available for this variant.
Still missing
- No functional data available.
Sources
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation data available.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. POLE has well-established pathogenic missense variants in the exonuclease domain (e.g., P286R, V411L, S297F, A456P, S459F) and disease is not exclusively caused by truncating variants. Therefore BP1 is not applicable to POLE missense variants. Details ▾Hide ▴
Evidence considered
- POLE disease mechanism includes pathogenic missense variants
- not exclusively a truncating-variant disease gene.
Sources
pvs1_gene_contextvcep_path_250_323
BP2 No evidence of this variant being observed in trans with a known pathogenic POLE variant. POLE-associated disease (polymerase proofreading-associated polyposis, PPAP) is autosomal dominant with incomplete penetrance; observation in trans with a pathogenic variant would be informative but none is reported. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
Still missing
- No data on co-occurrence with pathogenic POLE variants.
BP4 Under the León-Castillo et al. 2020 custom POLE framework, BP4_Supporting requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and benign in silico results ≥4. R1579C is absent from both tables. Under generic ACMG, computational evidence is mixed rather than showing a consensus benign prediction: REVEL 0.412 (intermediate), BayesDel 0.071 (benign-leaning but not strongly so), SpliceAI max delta 0.20. Multiple lines of evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.412 (intermediate
- not clearly benign)
- BayesDel 0.071 (benign-leaning)
- SpliceAI 0.20 (borderline)
- variant absent from León-Castillo Tables S2/S3.
Sources
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease. No reports of this variant co-occurring with a solved molecular diagnosis. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis identified for individuals carrying this variant.
Still missing
- No data on co-occurrence with alternate molecular diagnoses.
BP6 No reputable source has reported this variant as benign. ClinVar classification is 'Uncertain significance' (VariationID 405672), not benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS
- no reputable source has classified this variant as benign.
Sources
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is 'Uncertain significance' (VariationID 405672, three clinical laboratories, review status: criteria provided, single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS
- no expert panel or multiple-submitter pathogenic classification.
Sources
Not assessed · 1 · no assessment recorded
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. POLE is a large gene with both missense and truncating pathogenic variants. Region-specific missense constraint data for the C-terminal domain (where R1579 resides) are not established. This criterion is deferred for lack of domain-specific constraint metrics. Details ▾Hide ▴
Evidence considered
- POLE has established pathogenic missense variants in the exonuclease domain but not at this C-terminal location
- no domain-specific missense constraint data available.
Still missing
- No gene-level or domain-level missense Z-score for POLE C-terminal domain.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.4735C>T, p.Arg1579Cys), not a null variant (nonsense, frameshift, or canonical ±1/2 splice site). PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 1579
- PVS1 decision tree variant bucket classified as 'other'
- generic PVS1 framework not activated.
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/ASkipped per instructions — trivially not applicable (no recessive inheritance context for POLE). Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instructions — trivially not applicable (not an in-frame deletion/insertion or stop-loss variant). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants with confirmed pathogenicity were identified at Arg1579. The automated PM5 candidate harvest found zero candidates and recommended not_applicable. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidates found
- residue Arg1579 has no established pathogenic missense comparators in ClinVar.
Sources
pm5_candidates
BP3 N/ASkipped per instructions — trivially not applicable (in-frame deletions/insertions in non-repeat regions). Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants not predicted to affect splicing. This is a missense variant (c.4735C>T, p.Arg1579Cys) and therefore BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.3
- Coding (HGVS c.)
- NM_006231.3:c.4735C>T
- Protein (HGVS p.)
- NP_006222.2:p.(Arg1579Cys)
- GRCh38
- chr12:132642723 G>A
- GRCh37
- chr12:133219309 G>A
- ClinVar
- 405672
- COSMIC
- COSV57690476
Gene diagram
Every interpreted variant in POLE, mapped onto the exon structure of NM_006231.3. Select a row to find it on the plot.
POLENM_006231.3
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
8 / 1,613,270 alleles
AF 4.96e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD v2.1
1 / 31,386 alleles
AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,613,270 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)8 / 1,179,654 | 6.8e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,386 alleles · 0 hom
| European (non-Finnish)1 / 15,418 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.412
- BayesDel
- 0.071
How the predictions were used
PP3 Under the León-Castillo et al. 2020 custom POLE framework, PP3_Supporting requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and benign in silico results ≤1. R1579C is absent from both tables. Under generic ACMG, the computational evidence is mixed and does not support a deleterious effect: REVEL score is 0.412 (intermediate, below typical pathogenic threshold of 0.5), BayesDel score is 0.071 (benign-leaning), and SpliceAI max delta is 0.20 (borderline). Multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.412 (intermediate)
- BayesDel 0.071 (benign-leaning)
- SpliceAI max delta 0.20 (borderline)
- variant absent from León-Castillo Tables S2 and S3.
Sources
BP4 Under the León-Castillo et al. 2020 custom POLE framework, BP4_Supporting requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and benign in silico results ≥4. R1579C is absent from both tables. Under generic ACMG, computational evidence is mixed rather than showing a consensus benign prediction: REVEL 0.412 (intermediate), BayesDel 0.071 (benign-leaning but not strongly so), SpliceAI max delta 0.20. Multiple lines of evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL 0.412 (intermediate
- not clearly benign)
- BayesDel 0.071 (benign-leaning)
- SpliceAI 0.20 (borderline)
- variant absent from León-Castillo Tables S2/S3.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants not predicted to affect splicing. This is a missense variant (c.4735C>T, p.Arg1579Cys) and therefore BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.412. BayesDel score = 0.0712825.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 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.Hampel H et al. · 2015A practice guideline from ACMG and NSGC establishing referral indications for cancer predisposition assessment. Discusses referral criteria for hereditary cancer syndromes including Lynch, HBOC, FAP, and others. NM_006231.3:c.4735C>T (POLE p.Arg1579Cys) is not mentioned in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,613,270 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.200
Open source ↗
ClinVar
3 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/405672/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133219309-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132642723-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132642723-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.3%3Ac.4735…
- OncoKB ↗www.oncokb.org/gene/POLE/R1579C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126860089
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57690476, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.