About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.6816G>A, p.(Glu2272=)
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
NM_006231.4:c.6816G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 frequency threshold of <0.1% in population databases.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
NM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) located in exon 49 (42 nucleotides from the acceptor site, 1007 nucleotides from the donor site). SpliceAI predicts no splicing impact (max delta score 0.00, all delta scores at 0.00). The variant is far from splice consensus sequences and does not create a novel splice site.
Recorded classification: Uncertain significance
The custom POLE framework (Leon-Castillo et al. 2020) uses standard ACMG/AMP 2015 final combination rules. Only two criteria are met: PM2 at supporting strength and BP7 at supporting benign strength. This combination does not satisfy any pathogenic, likely pathogenic, benign, or likely benign threshold. With one pathogenic supporting and one benign supporting criterion — conflicting and insufficient evidence — the variant defaults to Variant of Uncertain Significance (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
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
2 reported laboratory submissions
2 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57678650, n = 1 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.
26 criteria with recorded statuses: 2 met · 18 not met · 0 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_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) in exon 49 of the DNA polymerase epsilon catalytic subunit gene POLE.
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 criterion at supporting strength.
SpliceAI predicts no splicing impact (max delta score 0.00) for this synonymous variant located deep within exon 49, satisfying BP7 at supporting benign strength.
This variant has been reported in ClinVar as Likely benign by two clinical laboratories (Variation ID 1146301, 1-star review status, criteria provided by a single submitter).
The León-Castillo et al. 2020 custom POLE framework, which provides gene-specific rules for PM1, PS4, PP3, and BP4, applies exclusively to exonuclease-domain missense variants and does not address this synonymous variant at codon 2272, which lies outside the exonuclease domain (residues 268–471).
The variant has been observed once in somatic cancers (COSMIC COSV57678650) but has not been identified as a recurrent somatic hotspot or as a germline disease-associated variant in the literature reviewed.
Overall, the variant meets PM2 (supporting) and BP7 (supporting benign), with all other assessed criteria not met or not applicable. With one pathogenic supporting and one benign supporting criterion, the evidence is insufficient for classification as either likely pathogenic or likely benign, resulting in a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_006231.4:c.6816G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 frequency threshold of <0.1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- absent from gnomAD v4.1 (0 alleles)
- absent from gnomAD-Canada v1.0 (0 alleles).
Sources
BP7 SupportingNM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) located in exon 49 (42 nucleotides from the acceptor site, 1007 nucleotides from the donor site). SpliceAI predicts no splicing impact (max delta score 0.00, all delta scores at 0.00). The variant is far from splice consensus sequences and does not create a novel splice site. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.Glu2272=
- SpliceAI max delta 0.00 with no predicted acceptor gain
- acceptor loss
- donor gain
- or donor loss
- position deep within exon 49 far from splice junctions.
Still missing
- No phyloP or GERP nucleotide conservation scores available to confirm the nucleotide is not highly conserved.
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in case materials.
Still missing
- No parental testing or de novo study data available.
PS3 No functional studies have been performed on NM_006231.4:c.6816G>A. This synonymous variant at codon 2272 is outside the POLE exonuclease domain (residues 268–471) and is not represented in the León-Castillo et al. 2020 endometrial carcinoma cohorts, which focus exclusively on exonuclease-domain missense variants. Details ▾Hide ▴
Evidence considered
- Variant is synonymous and outside the exonuclease domain
- not listed in any León-Castillo supplementary table
- no REVEL/BayesDel scores available (inapplicable to synonymous variants).
Still missing
- No functional data exists for this variant.
Sources
vcep_path_250_323vcep_path_250_323_s002vcep_path_250_323_s003vcep_path_250_323_s004
PS4 The custom POLE framework PS4 rule (León-Castillo et al. 2020) requires the variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10 and belong to the established pathogenic hotspot set. This synonymous variant is absent from Supplementary Table S1. Generic PS4 case-control evidence is also absent. Details ▾Hide ▴
Evidence considered
- Variant not found in Supplementary Table S1
- COSMIC reports a single somatic observation (COSV57678650) insufficient for PS4
- no germline case-control data.
Still missing
- No case-control or cohort enrichment data.
Sources
vcep_path_250_323_s002
PM1 The custom POLE framework PM1 rules apply exclusively to specific exonuclease-domain missense hotspot variants (P286R, V411L, S297F, A456P, S459F at strong; F367S, L424I, M295R, P436R, M444K, D368Y at moderate; A465V, L424V, T278M, A428T at supporting). This synonymous variant at codon 2272 is far outside the exonuclease domain (residues 268–471) and is not listed in any tier. The variant also does not lie in a statistically significant hotspot at cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Codon 2272 is C-terminal to the exonuclease domain
- variant absent from León-Castillo hotspot lists
- not in cancerhotspots.org significant hotspots.
Sources
vcep_path_250_323vcep_path_250_323_s002
PM6 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in case materials.
Still missing
- No de novo testing data available.
PP1 No segregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data provided.
Still missing
- No segregation analysis data.
PP3 The custom POLE framework PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This synonymous variant is absent from both tables. Under generic fallback: SpliceAI predicts no splicing impact (max delta 0.00), REVEL and BayesDel scores are not available for synonymous variants, and no multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- Variant not found in Supplementary Tables S2 or S3
- SpliceAI max delta score 0.00 predicts no splicing impact
- REVEL/BayesDel not applicable for synonymous variants.
Sources
PP4 No patient phenotype or family history data specific to this variant are available for assessment. Details ▾Hide ▴
Evidence considered
- No proband phenotype information provided in case materials.
Still missing
- No patient-specific phenotypic data.
PP5 ClinVar reports this variant as Likely benign, not Pathogenic/Likely pathogenic. Additionally, the review status is 1-star (criteria provided, single submitter), which does not meet the 3-star expert panel threshold required for PP5 at supporting strength. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely benign (1-star
- 2 clinical laboratories)
- PP5 requires pathogenic classification from a reputable source with supporting evidence.
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in gnomAD v2.1 and v4.1
- BA1 threshold is >1%.
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0%, which does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in gnomAD
- BS1 threshold is >0.3%.
Sources
BS2 No data on observation of this variant in healthy adult controls are available. Details ▾Hide ▴
Evidence considered
- No healthy control observation data provided.
Still missing
- No control cohort data for this variant.
BS3 No well-established functional studies have been performed on NM_006231.4:c.6816G>A demonstrating no damaging effect. Details ▾Hide ▴
Evidence considered
- No functional studies available for this synonymous variant.
Still missing
- No functional data exists for this variant.
BS4 No segregation data are available to demonstrate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation analysis data provided.
Still missing
- No family segregation data.
BP2 No data on observation of this variant in trans with a pathogenic variant are available. Details ▾Hide ▴
Evidence considered
- No trans-configuration data provided.
Still missing
- No phase data with pathogenic variants.
BP4 The custom POLE framework BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; this synonymous variant is absent from both tables. Under generic fallback: while SpliceAI predicts no splicing impact, additional computational evidence lines (conservation scores, REVEL/BayesDel) are unavailable for this synonymous variant. BP7 is the more specific criterion applied for the synonymous variant with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant absent from Supplementary Tables S2/S3
- SpliceAI max delta 0.00
- no REVEL/BayesDel applicable
- evidence applied through BP7 instead.
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data provided.
Still missing
- No data on alternate molecular diagnoses.
BP6 ClinVar reports this variant as Likely benign with a 1-star review status (criteria provided, single submitter). The 3-star expert panel threshold required for BP6 at supporting strength is not met, per the global PP5/BP6 rule requiring ClinVar 3-star expert panel status. Details ▾Hide ▴
Evidence considered
- ClinVar Likely benign
- 2 clinical laboratories
- 1-star review status
- BP6 at supporting requires 3-star expert panel.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) that does not result in a null variant (nonsense, frameshift, or canonical splice site disruption). The generic PVS1 framework does not apply to synonymous variants. Details ▾Hide ▴
Evidence considered
- Synonymous variant with no predicted amino acid change
- variant_bucket is 'other'
- generic PVS1 framework not applicable per PMC6185798.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ASynonymous variant does not alter the amino acid; PS1 requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- p.Glu2272= is a synonymous change with no amino acid alteration.
PM5 N/ASynonymous variant with no amino acid change; PM5 requires a different missense change at the same codon. The PM5 candidate harvesting pipeline confirmed no classic same-residue candidates are available. Details ▾Hide ▴
Evidence considered
- p.Glu2272= is synonymous
- no amino acid residue to assess for alternate pathogenic missense changes. PM5 candidate pipeline confirms eligible_for_classic_pm5_search = false.
Sources
pm5_candidates
PP2 N/ASynonymous variant, not a missense change. PP2 applies to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- p.Glu2272= is synonymous
- not missense.
BP1 N/ASynonymous variant, not a missense change. BP1 applies to missense variants in genes where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- p.Glu2272= is synonymous
- not missense.
PS5 N/ASynonymous variant with no amino acid change; PS5 requires a novel missense change at a residue where a different pathogenic missense has been established. Details ▾Hide ▴
Evidence considered
- p.Glu2272= is synonymous
- no missense change to compare.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.6816G>A
- Protein (HGVS p.)
- NP_006222.2:p.(Glu2272=)
- GRCh38
- chr12:132624742 C>T
- GRCh37
- chr12:133201328 C>T
- ClinVar
- 1146301
- COSMIC
- COSV57678650
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
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
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingNM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) located in exon 49 (42 nucleotides from the acceptor site, 1007 nucleotides from the donor site). SpliceAI predicts no splicing impact (max delta score 0.00, all delta scores at 0.00). The variant is far from splice consensus sequences and does not create a novel splice site. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.Glu2272=
- SpliceAI max delta 0.00 with no predicted acceptor gain
- acceptor loss
- donor gain
- or donor loss
- position deep within exon 49 far from splice junctions.
Still missing
- No phyloP or GERP nucleotide conservation scores available to confirm the nucleotide is not highly conserved.
Sources
PP3 The custom POLE framework PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This synonymous variant is absent from both tables. Under generic fallback: SpliceAI predicts no splicing impact (max delta 0.00), REVEL and BayesDel scores are not available for synonymous variants, and no multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- Variant not found in Supplementary Tables S2 or S3
- SpliceAI max delta score 0.00 predicts no splicing impact
- REVEL/BayesDel not applicable for synonymous variants.
Sources
BP4 The custom POLE framework BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; this synonymous variant is absent from both tables. Under generic fallback: while SpliceAI predicts no splicing impact, additional computational evidence lines (conservation scores, REVEL/BayesDel) are unavailable for this synonymous variant. BP7 is the more specific criterion applied for the synonymous variant with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant absent from Supplementary Tables S2/S3
- SpliceAI max delta 0.00
- no REVEL/BayesDel applicable
- evidence applied through BP7 instead.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp et al. 2017 describe the Sherloc refinement of the ACMG-AMP variant classification criteria. This is a general methodological framework paper and does not discuss NM_006231.4:c.6816G>A or any specific POLE variants.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 0.000
Open source ↗
ClinVar
2 Likely benign
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_006231.4%3Ac.6816G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133201328-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132624742-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132624742-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.6816…
- OncoKB ↗www.oncokb.org/gene/POLE/E2272=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126837292
- 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 Likely benign (2 clinical laboratories). (ClinVarID = 1146301)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57678650, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.