About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.3799G>A, p.(Glu1267Lys)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (AF < 0.1%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The León-Castillo custom POLE framework BP4 rule requires the variant to be in Supplementary Table S2/S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; the variant is absent from the tables, falling back to generic assessment. Multiple lines of computational evidence suggest a benign impact: REVEL score 0.262 (benign-leaning), BayesDel score 0.061 (strongly benign-leaning), and SpliceAI max delta 0.07 (no predicted splice impact). Multiple in silico tools concordantly predict no damaging effect.
Recorded classification: Uncertain significance
Only one pathogenic supporting criterion (PM2_Supporting: absent from gnomAD) and one benign supporting criterion (BP4_Supporting: benign in silico predictions) are met. No very strong, strong, or moderate criteria are met. Under the León-Castillo et al. 2020 custom POLE framework (which retains standard ACMG/AMP 2015 final combination thresholds), a single supporting criterion is insufficient to reach Pathogenic, Likely Pathogenic, Likely Benign, or Benign. The presence of conflicting PM2_Supporting (pathogenic direction) and BP4_Supporting (benign direction) evidence results in 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/244852 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2_Supporting is met: NM_006231.3:c.3799G>A (p.Glu1267Lys) is absent from gnomAD v2.1 (0/244,852 alleles), v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1%.
BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL score 0.262, BayesDel score 0.061, and SpliceAI max delta 0.07 (no splice impact).
PVS1 is not applicable: this is a missense variant outside the scope of the ClinGen SVI PVS1 null-variant framework (PMC6185798).
The variant is absent from ClinVar, COSMIC, and cancerhotspots.org. No variant-specific functional data or literature reports were identified.
The León-Castillo et al. 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) were assessed: the variant is not in the exonuclease domain, not recurrent in EC cohorts, and absent from Supplementary Tables S1-S3.
Overall, with only PM2_Supporting and BP4_Supporting met, and all other criteria not met or not applicable, this variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (AF < 0.1%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/244
- 852 alleles
- AF = 0.000%
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingThe León-Castillo custom POLE framework BP4 rule requires the variant to be in Supplementary Table S2/S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; the variant is absent from the tables, falling back to generic assessment. Multiple lines of computational evidence suggest a benign impact: REVEL score 0.262 (benign-leaning), BayesDel score 0.061 (strongly benign-leaning), and SpliceAI max delta 0.07 (no predicted splice impact). Multiple in silico tools concordantly predict no damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.262 (benign-leaning)
- BayesDel score: 0.061 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact)
- Concordant benign predictions across multiple in silico tools
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No alternative nucleotide change at c.3799 has been reported as pathogenic. The variant is absent from ClinVar and no literature reports a different pathogenic substitution at this position. Details ▾Hide ▴
Evidence considered
- No other c.3799 substitution identified in ClinVar or literature
- Variant is absent from all population and clinical databases
Sources
PS2 No de novo observation has been reported for this variant. No proband genotype data, parental studies, or family trios are available. Details ▾Hide ▴
Evidence considered
- No de novo report identified in ClinVar
- literature
- or any evidence source
Still missing
- No proband or family genotype data available
PS3 No variant-specific or range-based functional data exists for p.Glu1267Lys. The variant is absent from COSMIC, OncoKB contains no variant-specific functional evidence, and no publications testing POLE E1267K were identified. Details ▾Hide ▴
Evidence considered
- Absent from COSMIC (no somatic recurrence)
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data
- No literature with functional assays targeting this variant or residue
Still missing
- No functional assay data available for p.Glu1267Lys
Sources
PS4 The León-Castillo custom POLE framework requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10. p.Glu1267Lys is absent from Supplementary Table S1 and absent from COSMIC; no case-control prevalence data are available. Details ▾Hide ▴
Evidence considered
- Absent from León-Castillo Supplementary Table S1 (recurrent EC variants)
- Absent from COSMIC
- Absent from ClinVar
Still missing
- No case-control or cohort prevalence data
Sources
vcep_path_250_323_s002clinvar ↗
PM1 The León-Castillo custom POLE framework restricts PM1 to exonuclease-domain missense variants (residues ~1-471). p.Glu1267Lys is located at residue 1267 in the C-terminal polymerase region, far outside the exonuclease domain. It is not one of the five established pathogenic hotspot mutations (P286R, V411L, S297F, A456P, S459F) and is not recurrent in the EC cohorts; cancerhotspots.org does not identify residue 1267 as a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- Residue 1267 is outside the POLE exonuclease domain (~1-471)
- Not one of the five established exonuclease-domain hotspot mutations
- Not listed in cancerhotspots.org as a significant hotspot residue
- Absent from León-Castillo Supplementary Table S1
Sources
vcep_path_250_323_s002vcep_path_250_323
PM5 No pathogenic missense variant at the same codon (1267) was identified. PM5 candidate harvesting found zero same-residue ClinVar candidates, and ClinVar contains no entries at all for this variant or codon. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic missense variant identified at codon 1267 in ClinVar
- PM5 candidate search returned zero same-residue candidates
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation has been reported for this variant. No proband genotype data or parental confirmation studies are available. Details ▾Hide ▴
Evidence considered
- No de novo report identified in any evidence source
Still missing
- No proband genotype data or trio studies
PP1 No co-segregation data are available. No family studies or pedigrees have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation or family study data available
Still missing
- No family segregation data
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. No missense constraint data (HCI prior, Z-score) are available for POLE to support this criterion. Additionally, the variant lies outside the exonuclease domain where pathogenic missense clustering is well-established. Details ▾Hide ▴
Evidence considered
- No HCI prior probability available for this variant
- No gene-level missense constraint metric (Z-score) retrieved
Still missing
- No missense constraint data for POLE
PP3 The León-Castillo custom POLE framework PP3 rule requires the variant to be listed in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result; E1267K is absent from both tables. Under generic fallback, REVEL score 0.262 (benign-leaning), BayesDel 0.061 (benign-leaning), and SpliceAI max delta 0.07 (no splice impact) collectively do not support a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.262 (benign-leaning
- below typical pathogenic threshold of 0.5)
- BayesDel score: 0.061 (benign-leaning)
- SpliceAI max delta: 0.07 (no predicted splice impact)
- Variant absent from León-Castillo Supplementary Tables S2 and S3
Sources
PP4 No proband phenotype or clinical data have been provided. The patient's clinical presentation and family history are unknown. Details ▾Hide ▴
Evidence considered
- No phenotype
- clinical history
- or family history data available
Still missing
- No patient phenotype or clinical data provided
PP5 This variant is absent from ClinVar. There are no submissions or classifications from any reputable source to support PP5. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no variation ID
- no submissions
Still missing
- No ClinVar classification available
Sources
BA1 The variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0. Allele frequency does not exceed the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.000% (0/244
- 852)
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent
Sources
BS1 The variant is absent from all gnomAD populations. Allele frequency is 0.000% and does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.000% (0/244
- 852)
- No population exceeds 0.3% frequency
Sources
BS2 No homozygous observations exist in gnomAD (0 homozygotes across all populations). The variant has not been observed in a healthy adult homozygous state. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes across all populations
- No homozygous observations in any database
Sources
BS3 No well-established in vitro or in vivo functional studies exist showing that p.Glu1267Lys has no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- No functional assay data available for p.Glu1267Lys
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific data
Still missing
- No functional studies exist for this variant
Sources
BS4 No family segregation data are available. Lack of segregation in affected family members cannot be demonstrated. Details ▾Hide ▴
Evidence considered
- No family segregation or linkage data available
Still missing
- No family segregation data
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. In POLE, established pathogenic missense variants in the exonuclease domain are a recognized disease mechanism (e.g., P286R, V411L), so POLE does not meet the BP1 assumption that missense changes are less likely pathogenic. Details ▾Hide ▴
Evidence considered
- Pathogenic POLE exonuclease-domain missense variants are well-established
- BP1 is not appropriate for genes where missense is a known disease mechanism
Sources
vcep_path_250_323
BP2 No observation of this variant in trans with a pathogenic POLE variant has been reported. No phase data are available. Details ▾Hide ▴
Evidence considered
- No trans configuration data available
Still missing
- No phase data or observation in trans with pathogenic variant
BP5 No alternate molecular basis for disease has been identified in this case. No additional pathogenic variant in POLE or another gene explaining the phenotype has been reported. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis identified
Still missing
- No phenotype or alternate genetic finding reported
BP6 This variant is absent from ClinVar. There are no submissions or benign classifications from any reputable source to support BP6. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no variation ID
- no submissions
Still missing
- No ClinVar classification available
Sources
PS5 No ClinVar entry exists for this variant. No expert panel classification or reputable source has asserted pathogenicity. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no variation ID
- no submissions
Still missing
- No ClinVar entry or expert panel classification
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon deletions). NM_006231.3:c.3799G>A is a missense variant (p.Glu1267Lys) and does not fall into any null-variant bucket under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Glu1267Lys)
- not a predicted null variant
- ClinGen SVI PVS1 framework does not apply to missense substitutions
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_006231.3:c.3799G>A is a missense variant (p.Glu1267Lys), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant is missense (G>A substitution results in Glu→Lys amino acid change)
- BP7 is designed for synonymous variants only
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.3
- Coding (HGVS c.)
- NM_006231.3:c.3799G>A
- Protein (HGVS p.)
- NP_006222.2:p.(Glu1267Lys)
- GRCh38
- chr12:132649512 C>T
- GRCh37
- chr12:133226098 C>T
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
Allele count data not recorded
gnomAD v2.1
0 / 244,852 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v2.1
AF 0 · 0 / 244,852 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/244852 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.262
- BayesDel
- 0.061
How the predictions were used
BP4 SupportingThe León-Castillo custom POLE framework BP4 rule requires the variant to be in Supplementary Table S2/S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; the variant is absent from the tables, falling back to generic assessment. Multiple lines of computational evidence suggest a benign impact: REVEL score 0.262 (benign-leaning), BayesDel score 0.061 (strongly benign-leaning), and SpliceAI max delta 0.07 (no predicted splice impact). Multiple in silico tools concordantly predict no damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.262 (benign-leaning)
- BayesDel score: 0.061 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact)
- Concordant benign predictions across multiple in silico tools
Sources
PP3 The León-Castillo custom POLE framework PP3 rule requires the variant to be listed in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result; E1267K is absent from both tables. Under generic fallback, REVEL score 0.262 (benign-leaning), BayesDel 0.061 (benign-leaning), and SpliceAI max delta 0.07 (no splice impact) collectively do not support a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.262 (benign-leaning
- below typical pathogenic threshold of 0.5)
- BayesDel score: 0.061 (benign-leaning)
- SpliceAI max delta: 0.07 (no predicted splice impact)
- Variant absent from León-Castillo Supplementary Tables S2 and S3
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_006231.3:c.3799G>A is a missense variant (p.Glu1267Lys), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant is missense (G>A substitution results in Glu→Lys amino acid change)
- BP7 is designed for synonymous variants only
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.262. BayesDel score = 0.0614221.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 0.070
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_006231.3%3Ac.3799G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133226098-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132649512-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132649512-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.3%3Ac.3799…
- OncoKB ↗www.oncokb.org/gene/POLE/E1267K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.3799G%3EA
- 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
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/244852 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.262. BayesDel score = 0.0614221.
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.