About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.2083T>C, p.(Phe695Leu)
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 rare in population databases. In gnomAD v2.1 the allele frequency is 0.00320% (9/281330), and in gnomAD v4.1 it is 0.00329% (53/1612366), both well below the project's non-VCEP PM2 threshold of 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The local POLE BP4 rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; taken together, the available computational evidence argues against a damaging effect.
Recorded classification: Uncertain significance
León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final-combination thresholds with custom POLE criterion specifications
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
53 / 1,612,366 alleles
gnomAD v4.1: 53 / 1,612,366 alleles. Recorded AF 3.28709e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.19909e-05; MAF= 0.00320%, 9/281330 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139626; MAF= 0.01396%, 1/7162 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The POLE c.2083T>C (p.Phe695Leu; p.F695L) variant has not been identified as a recurrent POLE hotspot in the León-Castillo endometrial carcinoma datasets or Cancer Hotspots and has been reported in ClinVar mainly as uncertain significance, with some likely benign submissions.
This variant is rare in population databases, with an allele frequency of 0.00320% in gnomAD v2.1 and 0.00329% in gnomAD v4.1, both below the project's 0.1% PM2 threshold.
Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact (maximum delta score 0.08), REVEL is 0.322, and BayesDel is -0.367686.
No criteria match.
Met · 2
PM2 SupportingThis variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00320% (9/281330), and in gnomAD v4.1 it is 0.00329% (53/1612366), both well below the project's non-VCEP PM2 threshold of 0.1%. Details ▾Hide ▴
Rule
PM2_Supporting by generic rarity threshold
Evidence considered
- gnomAD v2.1 total AF 3.19909e-05.
- gnomAD v4.1 total AF 3.28709e-05.
Sources
BP4 SupportingThe local POLE BP4 rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; taken together, the available computational evidence argues against a damaging effect. Details ▾Hide ▴
Rule
BP4_Supporting by generic computational evidence
Evidence considered
- Variant absent from local POLE supplementary computational tables.
- SpliceAI max delta score 0.08.
- REVEL score 0.322.
- BayesDel score -0.367686.
Still missing
- No POLE-specific generic missense threshold set beyond the local supplementary-table rule was available.
Sources
Not met · 5 · evaluated, threshold not reached
PS4 The local POLE framework applies PS4 only to exact variants that are recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic hotspot set. p.Phe695Leu was not identified in the León-Castillo recurrent-variant table and is not part of the established hotspot set, so this criterion is not met. Details ▾Hide ▴
Rule
PS4_Supporting not met under León-Castillo 2020 custom POLE rule
Evidence considered
- Custom POLE PS4 rule is restricted to a small exact-variant hotspot set.
- The exact variant was absent from Supplementary Table S1 recurrence review.
Sources
final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002
PM1 The local POLE framework does not award PM1 simply for being in POLE. It is limited to specific exact exonuclease-domain hotspot or recurrent pathogenic substitutions from León-Castillo et al. p.Phe695Leu is not one of the framework-listed hotspot or recurrent pathogenic substitutions, and Cancer Hotspots did not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Rule
PM1 not met under León-Castillo 2020 custom POLE rule
Evidence considered
- Custom PM1 rule is limited to exact substitutions listed in the local POLE framework.
- Cancer Hotspots review reported no statistically significant hotspot for this variant.
Sources
PP3 The local POLE computational rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; these results do not support a deleterious computational effect. Details ▾Hide ▴
Rule
PP3 not met; custom rule unavailable and generic computational evidence not supportive
Evidence considered
- Variant absent from local POLE supplementary computational tables.
- SpliceAI max delta score 0.08.
- REVEL score 0.322.
- BayesDel score -0.367686.
Sources
BA1 This variant does not meet the benign stand-alone frequency threshold. The highest observed gnomAD population frequency is 0.01646% in gnomAD v4.1, which is well below the project's BA1 threshold of 1%. Details ▾Hide ▴
Rule
BA1 not met by generic frequency threshold
Evidence considered
- Highest observed gnomAD v4.1 population AF 0.000164636.
- gnomAD v2.1 and v4.1 overall frequencies remain very low.
Sources
BS1 This variant does not meet the strong benign frequency threshold. The highest observed gnomAD population frequency is 0.01646%, which is below the project's BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
BS1 not met by generic frequency threshold
Evidence considered
- Highest observed gnomAD v4.1 population AF 0.01646%.
- Overall population frequency remains below BS1 threshold.
Sources
Not assessed · 13 · no assessment recorded
PS1 No evidence was identified showing a different nucleotide change that produces the same POLE p.Phe695Leu protein change and is already established as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar record was reviewed
- but no same-amino-acid established pathogenic comparison was identified in the available materials.
Still missing
- Check whether another nucleotide substitution causing p.Phe695Leu has a classified pathogenic/likely pathogenic interpretation.
Sources
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified. Details ▾Hide ▴
Still missing
- Family-based de novo data were not available.
PS3 No variant-specific functional study demonstrating a damaging effect for p.Phe695Leu was identified in the reviewed evidence. Details ▾Hide ▴
Evidence considered
- Curated review did not identify variant-specific reviewed functional evidence.
Still missing
- Direct functional assay data for this exact variant were not available.
Sources
PM5 No evidence was identified that a different missense change at codon 695 is established as pathogenic or likely pathogenic for use as PM5. Details ▾Hide ▴
Evidence considered
- Reviewed materials did not identify a qualifying pathogenic missense comparison at the same residue.
Still missing
- Assess whether other codon 695 missense substitutions have established pathogenic classifications.
Sources
clinvar ↗vcep_path_250_323_s002
PM6 No assumed de novo occurrence data were identified. Details ▾Hide ▴
Still missing
- Family-based de novo data were not available.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- Segregation data in affected relatives were not available.
PP2 The reviewed evidence did not establish a gene-specific PP2 rule showing that POLE is a gene in which missense variation is a common mechanism with low background benign missense variation across the full protein. Details ▾Hide ▴
Evidence considered
- Local POLE framework customizes PM1
- PS4
- PP3
- and BP4 only.
Still missing
- A validated POLE-specific PP2 framework was not available.
Sources
final_classification_framework
PP4 No phenotype information was provided that is sufficiently specific for a POLE-related hereditary syndrome to support PP4. Details ▾Hide ▴
Still missing
- Detailed personal and family phenotype data were not available.
BS2 The reviewed evidence did not establish a validated BS2 framework for this hereditary cancer context, and the absence of homozygotes alone is not sufficient to use BS2. Details ▾Hide ▴
Evidence considered
- No homozygotes were reported in gnomAD v2.1 or v4.1.
Still missing
- A disease-specific BS2 framework and well-phenotyped unaffected carrier data were not available.
Sources
BS3 No variant-specific functional study showing normal or near-normal POLE function was identified. Details ▾Hide ▴
Evidence considered
- Curated review did not identify variant-specific reviewed functional evidence.
Still missing
- Direct functional assay data for this exact variant were not available.
Sources
BS4 No evidence showing lack of segregation with disease was identified. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
BP2 No phase or co-occurrence data were identified to support or refute BP2. Details ▾Hide ▴
Still missing
- Co-occurrence and phase data were not available.
BP5 No alternate molecular diagnosis or independent explanation for disease was provided for assessment under BP5. Details ▾Hide ▴
Still missing
- Clinical correlation and alternate-cause data were not available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical +/-1,2 splice variant. Details ▾Hide ▴
Rule
PVS1 not applicable for missense variant
Evidence considered
- Generic PVS1 scaffold classifies this variant outside default null-variant buckets.
Sources
PM3 N/APM3 is intended for recessive disorders with pathogenic variants observed in trans, and that evidence context was not applicable here. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is not a protein length-changing variant, so PM4 does not apply. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 is not used as an independent criterion because source-based assertions alone are not accepted as primary evidence here. Details ▾Hide ▴
BP1 N/ABP1 does not apply because missense variation is an established disease-relevant variant class in POLE. Details ▾Hide ▴
Evidence considered
- Local POLE framework is specifically built around missense hotspot and computational interpretation.
Sources
final_classification_frameworkvcep_path_250_323
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region, so BP3 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 is not used as an independent criterion because source-based assertions alone are not accepted as primary evidence here. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or intronic change predicted to have no splice impact, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is missense
- SpliceAI review is not sufficient to convert BP7 into an applicable criterion.
Sources
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.2083T>C
- Protein (HGVS p.)
- NP_006222.2:p.(Phe695Leu)
- GRCh38
- chr12:132668446 A>G
- GRCh37
- chr12:133245032 A>G
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
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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
53 / 1,612,366 alleles
AF 3.29e-05 · 0 homozygotes · FAF 9.22e-05
gnomAD v2.1
9 / 281,330 alleles
AF 3.2e-05 · 0 homozygotes · FAF 1.09e-05
By genetic ancestry
gnomAD v4.1
AF 3.3e-05 · 53 / 1,612,366 alleles · 0 hom · FAF 9.2e-05
| Middle Eastern1 / 6,074 | 0.00016 |
| African/African American12 / 74,864 | 0.00016 |
| East Asian4 / 44,814 | 8.9e-05 |
| South Asian4 / 90,848 | 4.4e-05 |
| Admixed American2 / 59,774 | 3.3e-05 |
| European (non-Finnish)29 / 1,179,132 | 2.5e-05 |
| Remaining individuals1 / 62,424 | 1.6e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 9 / 281,330 alleles · 0 hom · FAF 1.1e-05
| Remaining individuals1 / 7,162 | 0.00014 |
| African/African American2 / 24,936 | 8e-05 |
| South Asian2 / 30,356 | 6.6e-05 |
| East Asian1 / 19,874 | 5e-05 |
| European (non-Finnish)3 / 128,562 | 2.3e-05 |
0 alternate alleles recorded in 3 other groups: Admixed American, Ashkenazi Jewish, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.28709e-05; MAF= 0.00329%, 53/1612366 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.19909e-05; MAF= 0.00320%, 9/281330 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139626; MAF= 0.01396%, 1/7162 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThe local POLE BP4 rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; taken together, the available computational evidence argues against a damaging effect. Details ▾Hide ▴
Rule
BP4_Supporting by generic computational evidence
Evidence considered
- Variant absent from local POLE supplementary computational tables.
- SpliceAI max delta score 0.08.
- REVEL score 0.322.
- BayesDel score -0.367686.
Still missing
- No POLE-specific generic missense threshold set beyond the local supplementary-table rule was available.
Sources
PP3 The local POLE computational rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; these results do not support a deleterious computational effect. Details ▾Hide ▴
Rule
PP3 not met; custom rule unavailable and generic computational evidence not supportive
Evidence considered
- Variant absent from local POLE supplementary computational tables.
- SpliceAI max delta score 0.08.
- REVEL score 0.322.
- BayesDel score -0.367686.
Sources
BP7 N/AThis is a missense variant rather than a synonymous or intronic change predicted to have no splice impact, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is missense
- SpliceAI review is not sufficient to convert BP7 into an applicable criterion.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.322. BayesDel score = -0.367686.
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
53 / 1,612,366 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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/variation/240419/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133245032-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132668446-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.2083…
- OncoKB ↗www.oncokb.org/gene/POLE/F695L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.2083T%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
This variant is present in gnomAD v4.1 (AF= 3.28709e-05; MAF= 0.00329%, 53/1612366 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.19909e-05; MAF= 0.00320%, 9/281330 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139626; MAF= 0.01396%, 1/7162 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.322. BayesDel score = -0.367686.
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.