About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.1763T>C, p.(Val588Ala)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP, absence from large population databases supports pathogenicity at supporting strength for a gene where pathogenic missense variants are an established disease mechanism.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.26 (below 0.5 pathogenic threshold, consistent with benign), BayesDel score -0.437986 (negative, indicating tolerated/benign), and SpliceAI max delta score 0.00 (predicting no splice alteration). Three independent computational predictors converge on a benign interpretation, meeting the BP4 threshold.
Recorded classification: Not classified
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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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
In progress — evidence not uploaded yet.
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 · 7 not met · 1 not assessed · 16 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.1763T>C (p.Val588Ala) is a missense variant in POLE, the catalytic subunit of DNA polymerase epsilon. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
Multiple computational predictors suggest a benign effect: REVEL score 0.26, BayesDel score -0.437986, and SpliceAI delta score 0.00 (BP4_Supporting).
Residue 588 lies outside the POLE exonuclease domain (residues ~268–471) and is not one of the established pathogenic hotspot residues identified by León-Castillo et al. 2020. The variant is absent from COSMIC and has not been reported as a recurrent somatic mutation in endometrial carcinoma.
No variant-specific functional data, de novo observations, co-segregation data, or ClinVar classifications were identified for this variant. OncoKB reports an unknown oncogenic effect with no variant-level curated evidence.
The overall evidence profile yields PM2_Supporting (1 pathogenic supporting criterion) and BP4_Supporting (1 benign supporting criterion). These offset to a variant of uncertain significance (VUS) per ACMG/AMP 2015 classification rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP, absence from large population databases supports pathogenicity at supporting strength for a gene where pathogenic missense variants are an established disease mechanism. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada v1.0 (0 alleles).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.26 (below 0.5 pathogenic threshold, consistent with benign), BayesDel score -0.437986 (negative, indicating tolerated/benign), and SpliceAI max delta score 0.00 (predicting no splice alteration). Three independent computational predictors converge on a benign interpretation, meeting the BP4 threshold. Details ▾Hide ▴
Evidence considered
- REVEL 0.26 (benign)
- BayesDel -0.437986 (benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
Not met · 7 · evaluated, threshold not reached
PS3 No variant-specific functional data identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. V588A is absent from the León-Castillo et al. 2020 supplementary tables (S1–S3) and was not identified in any published functional study. No systematic range characterization encompassing residue 588 was found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect with no variant-specific evidence
- absent from León-Castillo supplementary tables S1–S3.
Still missing
- No functional studies available for this variant or a systematically characterized range including residue 588.
Sources
oncokb ↗vcep_path_250_323
PS4 Under the Leon-Castillo custom framework, PS4_Supporting requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10, which V588A does not satisfy (absent from COSMIC and supplementary tables). Under generic ACMG, no case-control or observational data exist to support increased prevalence in affected individuals. Details ▾Hide ▴
Evidence considered
- V588A absent from COSMIC
- absent from León-Castillo Supplementary Table S1 (recurrent POLE variants).
Still missing
- No case-control or cohort data available.
Sources
vcep_path_250_323_s002
PM1 Residue 588 lies outside the POLE exonuclease domain (residues ~268–471). V588A is not one of the established hotspot mutations in the León-Castillo custom framework (P286R, V411L, S297F, A456P, S459F for Strong; F367S, L424I, M295R, P436R, M444K, D368Y for Moderate; A465V, L424V, T278M, A428T for Supporting). The variant is not located in a statistically significant cancer hotspot per cancerhotspots.org. No critical functional domain characterized in the literature encompasses this residue. Details ▾Hide ▴
Evidence considered
- Not a cancer hotspot
- outside exonuclease domain
- absent from León-Castillo hotspot lists.
Sources
vcep_path_250_323vcep_path_250_323_s002
PP3 V588A is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic ACMG, REVEL score 0.26 (below pathogenic threshold of 0.5) and BayesDel score -0.437986 (benign range) do not support a damaging prediction. Multiple in silico tools predict a tolerated or benign effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.26 (benign)
- BayesDel -0.437986 (benign)
- absent from León-Castillo in silico tables S2 and S3.
Sources
revelbayesdelvcep_path_250_323_s003vcep_path_250_323_s004
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0%). This is well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD populations.
Sources
BS1 Variant is absent from gnomAD (allele frequency 0%). This is below the BS1 threshold of >0.3% for a gene where pathogenic missense variants are observed. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD populations.
Sources
BS3 No functional studies demonstrating a neutral or benign effect for this variant. No variant-specific functional data identified in the literature, OncoKB, or the León-Castillo supplementary materials. Details ▾Hide ▴
Evidence considered
- No functional data demonstrating benign effect
- OncoKB: Unknown Oncogenic Effect.
Still missing
- No functional studies available.
Sources
oncokb ↗vcep_path_250_323
Not assessed · 1 · no assessment recorded
PP2 While POLE has established pathogenic missense variants (exonuclease domain hotspots) supporting that missense changes are a disease mechanism, the HCI prior constraint data is unavailable for this transcript, precluding reliable assessment of the gene's rate of benign missense variation. PP2 cannot be applied without constraint metrics. Details ▾Hide ▴
Evidence considered
- POLE has pathogenic missense mechanism
- but HCI prior data unavailable for constraint assessment.
Still missing
- HCI prior constraint data not available
- cannot evaluate benign missense rate.
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_006231.3:c.1763T>C is a missense substitution (p.Val588Ala) and does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant outside PVS1 null-variant scope.
Sources
pvs1_generic_framework
PS1 N/ANo known pathogenic variant with the same amino acid change (p.Val588Ala) has been identified. This variant is absent from ClinVar entirely; no prerequisite pathogenic comparator exists for PS1. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic comparator at this residue.
Sources
PS2 N/ANo de novo confirmation data available for this variant. No publications identified in the literature search. Details ▾Hide ▴
Evidence considered
- No de novo data found.
Still missing
- No parental testing data available.
PM5 N/ANo same-residue pathogenic comparator variants identified. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics; no ClinVar pathogenic variants at residue 588 were found. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator available.
PM6 N/ANo de novo data available for this variant. PM6 requires a confirmed de novo observation, and no such data were identified. Details ▾Hide ▴
Evidence considered
- No de novo observations identified.
Still missing
- No parental testing data.
PP1 N/ANo co-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data.
Still missing
- No family studies available.
PP4 N/ANo patient phenotype or clinical data available for specificity assessment. Details ▾Hide ▴
Evidence considered
- No phenotype data provided.
Still missing
- Patient phenotype not available.
PP5 N/AVariant is absent from ClinVar. No reputable source classification exists to support PP5. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no expert panel or reputable source classification.
Sources
BS2 N/AVariant has not been observed in any population database; cannot assess whether it has been seen in healthy adult individuals. BS2 requires observation in a healthy individual for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- Not observed in population databases
- no healthy individual data.
BS4 N/ANo family segregation data available to assess non-segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. POLE has well-established pathogenic missense variants (including the five exonuclease-domain hotspot mutations P286R, V411L, S297F, A456P, S459F), so the BP1 premise does not hold. Details ▾Hide ▴
Evidence considered
- POLE has known pathogenic missense mechanism
- BP1 premise not satisfied.
Sources
vcep_path_250_323
BP2 N/ANo data on observation in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans observation data.
BP5 N/AVariant is absent from ClinVar. No alternative molecular basis has been identified to explain the phenotype. Details ▾Hide ▴
BP6 N/AVariant is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_006231.3:c.1763T>C is a missense variant (p.Val588Ala), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies to synonymous variants only.
PS5 N/ANo established pathogenic missense variant has been identified at the same amino acid residue (Val588). ClinVar contains no entries for any POLE variant at this position, and PM5 candidate harvesting found no same-residue pathogenic comparators. Details ▾Hide ▴
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.3
- Coding (HGVS c.)
- NM_006231.3:c.1763T>C
- Protein (HGVS p.)
- NP_006222.2:p.(Val588Ala)
- GRCh38
- chr12:132672246 A>G
- GRCh37
- chr12:133248832 A>G
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
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
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
- 0.260
- BayesDel
- -0.438
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.26 (below 0.5 pathogenic threshold, consistent with benign), BayesDel score -0.437986 (negative, indicating tolerated/benign), and SpliceAI max delta score 0.00 (predicting no splice alteration). Three independent computational predictors converge on a benign interpretation, meeting the BP4 threshold. Details ▾Hide ▴
Evidence considered
- REVEL 0.26 (benign)
- BayesDel -0.437986 (benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
PP3 V588A is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic ACMG, REVEL score 0.26 (below pathogenic threshold of 0.5) and BayesDel score -0.437986 (benign range) do not support a damaging prediction. Multiple in silico tools predict a tolerated or benign effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.26 (benign)
- BayesDel -0.437986 (benign)
- absent from León-Castillo in silico tables S2 and S3.
Sources
revelbayesdelvcep_path_250_323_s003vcep_path_250_323_s004
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_006231.3:c.1763T>C is a missense variant (p.Val588Ala), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies to synonymous variants only.
Statement
In silico
In progress — evidence not uploaded yet.
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 0.000
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.1763T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133248832-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132672246-A-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132672246-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.3%3Ac.1763…
- OncoKB ↗www.oncokb.org/gene/POLE/V588A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.1763T%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
In progress — evidence not uploaded yet.
In silico
In progress — evidence not uploaded yet.
Functional
In progress — evidence not uploaded yet.
Somatic
In progress — evidence not uploaded yet.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Literature
In progress — evidence not uploaded yet.