About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.2778G>C, p.(Glu926Asp)
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 absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. The allele frequency is effectively zero in control populations, meeting the PM2 threshold for rare variants in population databases (<0.1%).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
No source classification-combination explanation was recorded.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 8 not met · 13 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006231.4:c.2778G>C (p.Glu926Asp) is a missense variant in exon 24 of POLE, located within the DNA polymerase domain (residues 393-1191). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).
The variant is not one of the established exonuclease-domain hotspot mutations (P286R, V411L, S297F, A456P, S459F) and does not appear in the León-Castillo et al. 2020 supplementary recurrence or in silico tables. It does not meet the custom POLE framework criteria for PM1, PS4, PP3, or BP4.
Computational predictions are equivocal: REVEL score of 0.281 is below pathogenic thresholds, BayesDel score of -0.171963 is benign-leaning, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple lines of in silico evidence do not support a deleterious effect (PP3 not met) but also do not convincingly support a benign effect (BP4 not met).
This variant has been reported in ClinVar as Uncertain significance (Variation ID 3225427) by a single clinical laboratory. No variant-specific functional studies, segregation data, or case-control evidence were identified.
The only publication associated with this variant (PMID:25394175) is an ACMG/NSGC practice guideline on cancer predisposition referral indications that does not mention this specific variant and does not provide variant-level evidence (PP5 not met).
With only PM2_Supporting met and no other pathogenic or benign criteria triggered, this variant remains a Variant of Uncertain Significance (VUS) under the León-Castillo 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. The allele frequency is effectively zero in control populations, meeting the PM2 threshold for rare variants in population databases (<0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 926 resulting in the same amino acid substitution (p.Glu926Asp) that has been previously classified as pathogenic. No same-amino-acid comparator identified. Details ▾Hide ▴
Still missing
- No known pathogenic variant with a different nucleotide change producing p.Glu926Asp
PS4 Under León-Castillo 2020 custom POLE framework, PS4_Supporting requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined EC count ≥10. NM_006231.4:c.2778G>C (p.E926D) is absent from Supplementary Table S1. Under generic ACMG/AMP, no case-control data demonstrating enrichment in affected individuals versus controls is available. ClinVar reports a single submitter classifying as VUS, without case-level evidence. Details ▾Hide ▴
Evidence considered
- Variant absent from León-Castillo Supplementary Table S1 (EC cohorts in COSMIC/TCGA)
- ClinVar: Uncertain significance
- single submitter
- no case-control data
- No germline case-control enrichment data available
Still missing
- No case-control study comparing frequency in affected vs unaffected individuals
- No large cohort study with penetrance estimates for this variant
Sources
clinvar ↗vcep_path_250_323_s002
PM1 Under León-Castillo 2020 custom framework, PM1 rules apply only to specified exonuclease-domain variants (Strong: P286R, V411L, S297F, A456P, S459F; Moderate: F367S, L424I, M295R, P436R, M444K, D368Y; Supporting: A465V, L424V, T278M, A428T). p.Glu926Asp is not among these and is absent from Supplementary Table S1. Under generic ACMG, residue 926 lies within the DNA polymerase domain (aa 393-1191), not the exonuclease hotspot domain (aa 1-392) where established pathogenic missense variants cluster. No evidence of a mutational hotspot at this position. Details ▾Hide ▴
Evidence considered
- León-Castillo custom PM1 rules: variant not in any specified PM1 tier
- Residue 926 is in DNA polymerase domain
- not exonuclease hotspot domain
- Not recurrent in COSMIC/TCGA EC cohorts (absent from Table S1)
Still missing
- No mutational hotspot or critical functional domain established at residue 926
Sources
vcep_path_250_323_s002vcep_path_250_323
PP3 Under León-Castillo 2020 custom framework, PP3_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and benign in silico count ≤1. p.E926D is absent from both tables. Under generic ACMG, REVEL score 0.281 is below typical pathogenic thresholds; BayesDel score -0.171963 is negative, suggesting a benign-leaning prediction; SpliceAI max delta 0.01 indicates no splicing impact. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.281 (below pathogenic threshold)
- BayesDel: -0.171963 (benign-leaning)
- SpliceAI max delta: 0.01 (no splice impact)
- Variant absent from León-Castillo Tables S2 and S3
Sources
PP5 The sole ClinVar-attributed publication (PMID:25394175) is an ACMG/NSGC practice guideline on cancer predisposition referral indications. This paper does not mention NM_006231.4:c.2778G>C, p.Glu926Asp, or any POLE-specific variant. It does not constitute variant-specific reputable source evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- PMID:25394175 is a general practice guideline
- not variant-specific
- ClinVar classification: VUS (single submitter) — not a reputable pathogenic assertion
Still missing
- No variant-specific reputable source assertion
Sources
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BS1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BP4 Under León-Castillo 2020 custom framework, BP4_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.E926D is absent from both tables. Under generic ACMG, REVEL 0.281 is intermediate; BayesDel -0.171963 is mildly benign-leaning but not strongly predictive across multiple tools. Multiple lines of computational evidence do not convincingly suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.281 (intermediate
- not clearly benign)
- BayesDel: -0.171963 (mildly benign-leaning)
- Variant absent from León-Castillo Tables S2 and S3
Sources
revelbayesdelvcep_path_250_323_s003vcep_path_250_323_s004
Not assessed · 13 · no assessment recorded
PS2 No de novo data available for NM_006231.4:c.2778G>C in any reviewed source. No parental testing or confirmed de novo reports were identified. Details ▾Hide ▴
Still missing
- No de novo testing or parental genotype data available
PS3 No variant-specific functional studies identified for p.Glu926Asp. OncoKB reports no reviewed functional evidence for this variant. No publications with functional characterization of this exact substitution were found. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect — no variant-specific reviewed functional evidence
Still missing
- No functional assay data (enzymatic
- cellular
- or model organism) for p.Glu926Asp
Sources
PM6 No de novo data available. No confirmed de novo reports for NM_006231.4:c.2778G>C were identified in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No cosegregation data available for this variant. No family studies or segregation analysis were identified. Details ▾Hide ▴
Still missing
- No family segregation data
PP2 HCI prior data not available for this variant. Insufficient evidence to assess whether POLE has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. POLE has both pathogenic missense variants (exonuclease domain hotspots) and likely benign missense variants across the gene. Details ▾Hide ▴
Evidence considered
- HCI prior probability: not available for this variant
Still missing
- HCI prior data unavailable
- POLE gene-specific missense constraint metrics not assessed
PP4 No detailed phenotype or clinical specificity data available. The variant has been observed in clinical testing (ClinVar VUS, 1 submitter) but no specific phenotype information or syndromic features are documented. Details ▾Hide ▴
BS2 No data on observation in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy adult control observation data
BS3 No variant-specific functional studies demonstrating no deleterious effect for p.Glu926Asp. Details ▾Hide ▴
Still missing
- No functional studies demonstrating no protein impact
BS4 No cosegregation data available. No family studies demonstrating lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family cosegregation data
BP2 No data on observation in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
- No data on co-occurrence with pathogenic variants in trans
BP5 No observation of an alternate molecular basis for disease in individuals carrying this variant. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data
BP6 No reputable source has classified this variant as benign. ClinVar classification is VUS with a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- single submitter — no benign assertion from a reputable source
Still missing
- No expert panel or multiple submitters reporting as benign
Sources
PS5 No evidence from a reputable source recently submitted for pathogenicity assessment of this variant. ClinVar classification is VUS with criteria provided, single submitter — insufficient to meet PS5. Details ▾Hide ▴
Evidence considered
- ClinVar classification: VUS
- single submitter — does not constitute reputable pathogenic assertion
Still missing
- No reputable source asserting pathogenicity for this variant
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (NP_006222.2:p.Glu926Asp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice ±1/2); this variant falls into the 'other' bucket under the generic PVS1 decision tree (PMC6185798) and does not trigger PVS1. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- Not a null variant
- PVS1 decision tree places in 'other' bucket
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped — this is a substitution variant assessed in a gene not established as recessive. PM3 applies to variants in trans with pathogenic variants in recessive disorders. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped — this is a substitution variant. PM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants causing protein length change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ASame-residue missense comparator search could not identify a different pathogenic amino acid change at codon 926. The pm5_candidates pipeline found no candidates, and PM5 classic same-residue semantics could not be confirmed. Details ▾Hide ▴
Evidence considered
- No pathogenic missense comparator at codon 926 identified in ClinVar
Sources
pm5_candidates
BP1 N/APOLE has well-established pathogenic missense variants (e.g., exonuclease-domain hotspot mutations P286R, V411L, S297F, A456P, S459F). BP1 is intended for genes where disease is caused exclusively by truncating variants, which does not apply to POLE. Details ▾Hide ▴
Evidence considered
- POLE has established pathogenic missense variants in the exonuclease domain
Sources
vcep_path_250_323
BP3 N/ASkipped — this is a substitution variant. BP3 applies to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AMissense variant (c.2778G>C, p.Glu926Asp). BP7 applies to synonymous/silent variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.2778G>C
- Protein (HGVS p.)
- NP_006222.2:p.(Glu926Asp)
- GRCh38
- chr12:132661613 C>G
- GRCh37
- chr12:133238199 C>G
- ClinVar
- 3225427
Gene diagram
Every interpreted variant in POLE, mapped onto the exon structure of NM_006231.4. Select a row to find it on the plot.
POLENM_006231.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in POLE
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.281
- BayesDel
- -0.172
How the predictions were used
PP3 Under León-Castillo 2020 custom framework, PP3_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and benign in silico count ≤1. p.E926D is absent from both tables. Under generic ACMG, REVEL score 0.281 is below typical pathogenic thresholds; BayesDel score -0.171963 is negative, suggesting a benign-leaning prediction; SpliceAI max delta 0.01 indicates no splicing impact. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.281 (below pathogenic threshold)
- BayesDel: -0.171963 (benign-leaning)
- SpliceAI max delta: 0.01 (no splice impact)
- Variant absent from León-Castillo Tables S2 and S3
Sources
BP4 Under León-Castillo 2020 custom framework, BP4_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.E926D is absent from both tables. Under generic ACMG, REVEL 0.281 is intermediate; BayesDel -0.171963 is mildly benign-leaning but not strongly predictive across multiple tools. Multiple lines of computational evidence do not convincingly suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.281 (intermediate
- not clearly benign)
- BayesDel: -0.171963 (mildly benign-leaning)
- Variant absent from León-Castillo Tables S2 and S3
Sources
revelbayesdelvcep_path_250_323_s003vcep_path_250_323_s004
BP7 N/AMissense variant (c.2778G>C, p.Glu926Asp). BP7 applies to synonymous/silent variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.281. BayesDel score = -0.171963.
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. · 2015Practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. Does not mention POLE, NM_006231.4:c.2778G>C, p.Glu926Asp, or any specific gene variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 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/3225427/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133238199-C-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132661613-C-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132661613-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.2778…
- OncoKB ↗www.oncokb.org/gene/POLE/E926D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.2778G%3EC
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3225427)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.281. BayesDel score = -0.171963.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.