About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.3386A>G, p.(Asp1129Gly)
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 and extremely rare in gnomAD v4.1 (AF=2.48e-06, 4/1,613,948 alleles, no homozygotes). The allele frequency of 0.00025% is well below the 0.1% PM2 threshold. grpmax FAF is 7.9e-07.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Only one supporting-level pathogenic criterion (PM2_supporting) is met; no benign criteria are met. None of the ACMG/AMP 2015 pathogenic, likely pathogenic, benign, or likely benign combination rules are satisfied. Per the León-Castillo et al. 2020 custom POLE framework (which uses standard ACMG/AMP 2015 final classification thresholds), the evidence defaults to Variant of Uncertain Significance.
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
4 / 1,613,948 alleles
gnomAD v4.1: 4 / 1,613,948 alleles. Recorded AF 2.47839e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57675934, 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.
27 criteria with recorded statuses: 1 met · 16 not met · 7 not assessed · 3 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.3386A>G (p.Asp1129Gly) in POLE is a rare missense variant with an allele frequency of 0.00025% in gnomAD v4.1 (4/1,613,948 alleles, 0 homozygotes), meeting PM2 at supporting strength.
This variant is absent from gnomAD v2.1 and has a grpmax filtering allele frequency of 7.9e-07, consistent with a rare variant.
The variant has been reported as Uncertain significance in ClinVar (VariationID 934060) by a single clinical laboratory (Labcorp Genetics, SCV001373503).
This variant has previously been reported in somatic cancers (COSMIC COSV57675934, n=1).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
The variant is absent from the León-Castillo et al. 2020 supplementary tables of recurrent POLE endometrial carcinoma variants and does not map to any of the five established exonuclease-domain hotspot positions (P286R, V411L, S297F, A456P, S459F).
In silico predictions are conflicting: REVEL score of 0.797 is in the deleterious range but BayesDel score of 0.157532 is in the benign range, and HCI prior is not available, precluding application of PP3 or BP4.
OncoKB did not identify variant-specific reviewed functional evidence for p.Asp1129Gly.
Overall, only one supporting-level pathogenic criterion (PM2) is met. No benign criteria are met. The evidence is insufficient for a classification beyond Variant of Uncertain Significance under the custom POLE framework (León-Castillo et al. 2020).
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF=2.48e-06, 4/1,613,948 alleles, no homozygotes). The allele frequency of 0.00025% is well below the 0.1% PM2 threshold. grpmax FAF is 7.9e-07. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: AF=2.48e-06 (0.00025%)
- 4/1
- 613
- 948 alleles
- 0 homozygotes
- grpmax FAF=7.9e-07.
- Highest subpopulation AF: European (non-Finnish) 3.39e-06.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 No evidence was identified for a different nucleotide change at codon 1129 resulting in the same amino acid substitution (p.Asp1129Gly) with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar contains only NM_006231.4:c.3386A>G (VUS) at this codon.
Still missing
- No alternative nucleotide changes at codon 1129 producing D1129G were identified.
Sources
PS3 No variant-specific functional studies were identified for p.Asp1129Gly. The variant lies outside the POLE exonuclease domain (residues 268–471). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications in the case literature packet contain functional data for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- Variant (p.D1129G) is C-terminal to the exonuclease domain
- the León-Castillo framework does not cover this region.
Still missing
- No experimental functional characterization of p.Asp1129Gly.
Sources
oncokb ↗vcep_path_250_323
PS4 The León-Castillo custom POLE framework limits PS4_Supporting to four specific hotspot variants (p.P286R, p.V411L, p.A456P, p.S297F). p.Asp1129Gly is not among these. Under generic ACMG, a single COSMIC somatic observation (n=1) does not meet PS4 thresholds for statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- COSMIC COSV57675934: 1 somatic observation.
- Absent from Supplementary Table S1 recurrent EC variants.
- Custom PS4 rule restricts eligibility to specific exonuclease-domain hotspots only.
Still missing
- No case-control or cohort enrichment data.
Sources
vcep_path_250_323_s002
PM1 p.Asp1129 is located at position 1129, well outside the POLE exonuclease domain (residues 268–471). The León-Castillo custom framework assigns PM1 only to specific listed hotspot variants within the exonuclease domain. The position is not in a statistically significant hotspot per cancerhotspots.org. No critical functional domain has been characterized at this C-terminal region. Details ▾Hide ▴
Evidence considered
- Exonuclease domain: residues 268–471
- variant at position 1129 is outside this domain.
- Cancerhotspots.org: residue not significant.
- Absent from Supplementary Table S1 recurrent variant list.
- Custom PM1 rules restricted to specific exonuclease-domain variants only.
Sources
vcep_path_250_323_s002vcep_path_250_323
PM5 No comparator variant at codon 1129 with a different missense change and an established pathogenic classification was identified. The automated PM5 candidate search found zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned 0 same-residue candidates.
- ClinVar contains no other pathogenic missense variants at codon 1129.
Still missing
- No pathogenic comparator at codon 1129.
Sources
pm5_candidates
PP2 PP2 requires a missense variant in a gene where missense variants are a common disease mechanism and benign missense variation is rare. POLE is a large gene with many missense variants. The León-Castillo framework does not provide a gene-specific PP2 rule, and under generic ACMG criteria, this variant does not meet PP2 requirements. Details ▾Hide ▴
Evidence considered
- No POLE-specific PP2 rule in the custom framework.
- Generic PP2 not met — POLE has substantial benign missense variation.
PP3 The variant is absent from Supplementary Tables S2 and S3, so the custom POLE PP3 rule does not apply. Under generic ACMG, multiple lines of in silico evidence must support a deleterious effect. REVEL score of 0.797 is in the deleterious range, but BayesDel score of 0.157532 is in the benign range, and SpliceAI predicts no splicing impact (max delta 0.02). The conflicting in silico predictions do not satisfy the requirement for multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.797 (deleterious direction).
- BayesDel: 0.157532 (benign direction).
- SpliceAI: max delta 0.02 (no predicted impact).
- Absent from Supplementary Tables S2 and S3 — custom PP3 rule does not apply.
- HCI prior: not found.
Still missing
- Conflicting in silico evidence
- no consensus among predictors.
Sources
PP5 ClinVar reports this variant as Uncertain significance with a review status of criteria provided, single submitter (1-star). PP5 requires a 3-star expert panel classification as pathogenic; a single-submitter VUS classification does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 934060: Uncertain significance
- 1 submitter (Labcorp Genetics
- SCV001373503)
- criteria provided
- single submitter.
Sources
BA1 The allele frequency in gnomAD v4.1 is 0.00025% (AF=2.48e-06), far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 The allele frequency of 0.00025% is well below the 0.3% BS1 threshold. Details ▾Hide ▴
BS2 No homozygotes have been observed in gnomAD v2.1 or v4.1. BS2 requires observation in a healthy adult homozygous state. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 4 heterozygous alleles
- 0 homozygotes.
Still missing
- No homozygous observations.
Sources
BS3 No well-established functional studies demonstrating no deleterious effect were identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies available.
Still missing
- No functional characterization of p.Asp1129Gly.
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants are known to cause disease. POLE has well-established pathogenic missense variants within the exonuclease domain (e.g., P286R, V411L, S297F, A456P, S459F), so this criterion does not apply. Details ▾Hide ▴
Evidence considered
- POLE exonuclease-domain missense variants are established as pathogenic (P286R
- V411L
- S297F
- A456P
- S459F).
Sources
vcep_path_250_323
BP4 BP4 requires multiple lines of in silico evidence predicting no impact. The variant is absent from Supplementary Tables S2 and S3, so the custom BP4 rule does not apply. Under generic ACMG, REVEL score of 0.797 is in the deleterious range, contradicting a benign in silico prediction. Multiple predictors do not converge on a benign call. Details ▾Hide ▴
Evidence considered
- REVEL: 0.797 (deleterious direction).
- BayesDel: 0.157532 (benign direction but low confidence).
- SpliceAI: max delta 0.02 (no predicted impact).
- Absent from Supplementary Tables S2 and S3 — custom BP4 rule does not apply.
Sources
BP6 ClinVar reports this variant as Uncertain significance, not benign. BP6 requires a reputable source (3-star expert panel) to classify the variant as benign. A single-submitter VUS classification does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 934060: Uncertain significance
- 1 submitter
- criteria provided
- single submitter.
Sources
PS5 No established pathogenic variant at codon 1129 was identified from ClinVar or the literature. No comparator variant at this codon is available to support PS5. Details ▾Hide ▴
Evidence considered
- ClinVar contains only the queried variant at codon 1129.
Still missing
- No pathogenic variants reported at codon 1129.
Sources
Not assessed · 7 · no assessment recorded
PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data.
PM6 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data.
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data.
PP4 No phenotype or family history data specific to the proband are available. Details ▾Hide ▴
Still missing
- No proband phenotype data provided.
BS4 No cosegregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data.
BP2 No data on observations in trans with a pathogenic variant are available. Details ▾Hide ▴
Still missing
- No trans-phase observations.
BP5 No information about an alternative molecular cause of disease in the proband is available. Details ▾Hide ▴
Still missing
- No data on alternative molecular diagnoses.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Asp1129Gly) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessment
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense substitution (p.Asp1129Gly). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.3386A>G
- Protein (HGVS p.)
- NP_006222.2:p.(Asp1129Gly)
- GRCh38
- chr12:132657422 T>C
- GRCh37
- chr12:133234008 T>C
- ClinVar
- 934060
- COSMIC
- COSV57675934
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
4 / 1,613,948 alleles
AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,613,948 alleles · 0 hom · FAF 7.9e-07
| European (non-Finnish)4 / 1,179,960 | 3.4e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38995e-06; MAF= 0.00034%, 4/1179960 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.797
- BayesDel
- 0.158
How the predictions were used
PP3 The variant is absent from Supplementary Tables S2 and S3, so the custom POLE PP3 rule does not apply. Under generic ACMG, multiple lines of in silico evidence must support a deleterious effect. REVEL score of 0.797 is in the deleterious range, but BayesDel score of 0.157532 is in the benign range, and SpliceAI predicts no splicing impact (max delta 0.02). The conflicting in silico predictions do not satisfy the requirement for multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.797 (deleterious direction).
- BayesDel: 0.157532 (benign direction).
- SpliceAI: max delta 0.02 (no predicted impact).
- Absent from Supplementary Tables S2 and S3 — custom PP3 rule does not apply.
- HCI prior: not found.
Still missing
- Conflicting in silico evidence
- no consensus among predictors.
Sources
BP4 BP4 requires multiple lines of in silico evidence predicting no impact. The variant is absent from Supplementary Tables S2 and S3, so the custom BP4 rule does not apply. Under generic ACMG, REVEL score of 0.797 is in the deleterious range, contradicting a benign in silico prediction. Multiple predictors do not converge on a benign call. Details ▾Hide ▴
Evidence considered
- REVEL: 0.797 (deleterious direction).
- BayesDel: 0.157532 (benign direction but low confidence).
- SpliceAI: max delta 0.02 (no predicted impact).
- Absent from Supplementary Tables S2 and S3 — custom BP4 rule does not apply.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense substitution (p.Asp1129Gly). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.797. BayesDel score = 0.157532.
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 K et al. · 2017Describes the Sherloc variant classification framework, a refinement of ACMG-AMP guidelines. NM_006231.4:c.3386A>G (p.Asp1129Gly) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,613,948 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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/934060/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133234008-T-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132657422-T-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132657422-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.3386…
- OncoKB ↗www.oncokb.org/gene/POLE/D1129G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126850408
- 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= 2.47839e-06; MAF= 0.00025%, 4/1613948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38995e-06; MAF= 0.00034%, 4/1179960 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
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 = 934060)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.797. BayesDel score = 0.157532.
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 previously been reported in somatic cancers (COSMIC; COSV57675934, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.