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POLEc.2137G>AUncertain significance
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Variant interpretation report

POLE c.2137G>A, p.(Glu713Lys)

NM_006231.4:c.2137G>A NP_006222.2:p.(Glu713Lys) View identifiers
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.

About POLE

No gene-level summary was recorded for this case.

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 rare in population databases. Its allele frequency is 0.00081% in gnomAD v2.1 (2/247784) and 0.00031% in gnomAD v4.1 (5/1608750), both below the 0.1% PM2 threshold, and it is absent from gnomAD-Canada.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final classification thresholds with POLE-specific 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
5 / 1,608,750 alleles

gnomAD v4.1: 5 / 1,608,750 alleles. Recorded AF 3.108e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.07155e-06; MAF= 0.00081%, 2/247784 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.78209e-05; MAF= 0.00178%, 2/112228 alleles, homozygotes = 0); grpmax FAF= 2.96e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

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; COSV106057460, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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: 1 met · 7 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The POLE c.2137G>A (p.Glu713Lys; p.E713K) variant has not been identified as a recurrent somatic POLE hotspot in the endometrial carcinoma datasets summarized by León-Castillo et al. and has been reported in ClinVar as a variant of uncertain significance.

This variant is rare in population databases, with an allele frequency of 0.00081% (2/247784) in gnomAD v2.1 and 0.00031% (5/1608750) in gnomAD v4.1, and it is absent from gnomAD-Canada.

Computational evidence does not support a splice-disrupting effect, with a SpliceAI maximum delta score of 0.01, and the missense predictor scores are not strongly damaging (REVEL 0.246; BayesDel -0.033673).

Met · 1

PM2 SupportingThis variant is rare in population databases. Its allele frequency is 0.00081% in gnomAD v2.1 (2/247784) and 0.00031% in gnomAD v4.1 (5/1608750), both below the 0.1% PM2 threshold, and it is absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 8.07155e-06
  • gnomAD v4.1 AF 3.108e-06
  • Absent from gnomAD-Canada
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 7 · evaluated, threshold not reached

PS1 No evidence was identified that this nucleotide change produces the same amino acid change as an established pathogenic or likely pathogenic variant. Details ▾Hide ▴
Evidence considered
  • ClinVar reviewed for exact variant context
Still missing
  • No validated same-amino-acid pathogenic comparator was identified
Sources
clinvar ↗
PS4 Under the local POLE framework, PS4_Supporting requires the exact missense variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and to belong to the established pathogenic set. This variant was not identified in the supplementary recurrence table and does not meet that rule. Details ▾Hide ▴
Rule
POLE local custom PS4 somatic-recurrence rule
Evidence considered
  • Local POLE PS4 rule reviewed
  • Exact variant not found in Supplementary Table S1
Still missing
  • No qualifying case-control or qualifying somatic-recurrence evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s002
PM1 Under the local POLE framework, PM1 is restricted to specific exonuclease-domain hotspot or recurrent substitutions from León-Castillo et al. This variant is not one of the listed qualifying substitutions and was not identified as a hotspot in the reviewed somatic hotspot resources. Details ▾Hide ▴
Rule
POLE local custom PM1 hotspot rule
Evidence considered
  • Local POLE PM1 rule reviewed
  • Exact variant not found in Supplementary Table S1
  • Cancer Hotspots review did not show a hotspot row for E713
Still missing
  • No qualifying POLE hotspot or restricted-region evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s002hotspots ↗
PP3 Under the local POLE framework, PP3 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a 'likely disease causing' REVEL class and no more than one benign in silico result. This variant was not identified in those tables. In the generic computational review, REVEL is 0.246, BayesDel is -0.033673, and SpliceAI max delta score is 0.01, which do not provide a strong damaging computational signal. Details ▾Hide ▴
Rule
POLE local custom PP3 rule with generic computational fallback
Evidence considered
  • Exact variant not found in Supplementary Tables S2 or S3
  • REVEL 0.246
  • BayesDel -0.033673
  • SpliceAI max delta 0.01
Still missing
  • No qualifying POLE table-based PP3 evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004revelbayesdelspliceai ↗
BA1 The population frequency is far below the 1% BA1 threshold: 0.00081% in gnomAD v2.1 and 0.00031% in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.00081%
  • gnomAD v4.1 AF 0.00031%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The population frequency is below the 0.3% BS1 threshold: 0.00081% in gnomAD v2.1 and 0.00031% in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.00081%
  • gnomAD v4.1 AF 0.00031%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Under the local POLE framework, BP4 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a benign-leaning REVEL class and at least four benign in silico results. This variant was not identified in those tables. In the generic computational review, SpliceAI predicts no significant splice impact (max delta 0.01), but REVEL 0.246 and BayesDel -0.033673 do not by themselves provide sufficiently validated benign missense evidence to apply BP4. Details ▾Hide ▴
Rule
POLE local custom BP4 rule with generic computational fallback
Evidence considered
  • Exact variant not found in Supplementary Tables S2 or S3
  • SpliceAI max delta 0.01
  • REVEL 0.246
  • BayesDel -0.033673
Still missing
  • No qualifying POLE table-based BP4 evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗revelbayesdel

Not assessed · 12 · no assessment recorded

PS2 No confirmed de novo data were identified. Details ▾Hide ▴
Still missing
  • Parental testing and maternity/paternity confirmation not available
PS3 No variant-specific functional study demonstrating a damaging effect was identified. Details ▾Hide ▴
Evidence considered
  • Curated cancer database review did not identify variant-specific reviewed functional evidence
Still missing
  • Direct functional assay data for p.Glu713Lys were not identified
Sources
oncokb ↗
PM3 No evidence was identified for this variant occurring in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
  • Phase and recessive-case data not available
PM6 No assumed de novo data were identified. Details ▾Hide ▴
Still missing
  • Parental testing data not available
PP1 No segregation data were identified. Details ▾Hide ▴
Still missing
  • Family segregation data not available
PP2 No gene-specific evidence set was identified to support applying PP2 to this missense variant. Details ▾Hide ▴
Evidence considered
  • Local POLE framework customizes PM1
  • PS4
  • PP3
  • and BP4 only
Still missing
  • No validated POLE missense-enrichment rule for PP2 was identified
Sources
final_classification_framework
PP4 No phenotype or tumor signature data specific enough to support PP4 were identified. Details ▾Hide ▴
Still missing
  • Clinical phenotype and disease-specific specificity data not available
BS2 No evidence was identified showing this variant in well-phenotyped healthy individuals at a frequency sufficient for BS2. Details ▾Hide ▴
Evidence considered
  • Rare population observations only
Still missing
  • Healthy adult carrier evidence not available
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 No variant-specific functional study demonstrating a normal or benign effect was identified. Details ▾Hide ▴
Evidence considered
  • Curated cancer database review did not identify variant-specific reviewed functional evidence
Still missing
  • Direct benign functional assay data for p.Glu713Lys were not identified
Sources
oncokb ↗
BS4 No non-segregation data were identified. Details ▾Hide ▴
Still missing
  • Family study data not available
BP2 No phase data with another variant were identified. Details ▾Hide ▴
Still missing
  • Phase and second-variant data not available
BP5 No alternate molecular explanation data were identified for the observed condition. Details ▾Hide ▴
Still missing
  • Clinical and genotype context not available
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, or canonical ±1/2 splice-site variant, so the generic PVS1 loss-of-function framework does not apply. Details ▾Hide ▴
Evidence considered
  • Protein change p.Glu713Lys / p.E713K
  • Generic PVS1 scaffold marked this variant outside null-variant buckets
Sources
pvs1_variant_assessmentpvs1_gene_context
PM4 N/AThis is a missense substitution and does not produce a protein length change. Details ▾Hide ▴
Evidence considered
  • Protein change p.Glu713Lys
PM5 N/AAvailable review materials did not establish that classic same-residue PM5 logic can be safely applied for this POLE framework, and no validated same-residue comparator set was confirmed for this variant. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review marked classic PM5 semantics as unconfirmed
  • No comparator candidates harvested
Still missing
  • No approved same-residue comparator framework was confirmed
Sources
pm5_candidatesfinal_classification_framework
PP5 N/AAssertion-only pathogenic evidence was not used. ClinVar contains only non-expert uncertain-significance submissions for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: uncertain significance
  • criteria provided
  • single submitter
Sources
clinvar ↗
BP1 N/ABP1 was not applied because there is no evidence here that missense variation is generally a less relevant mechanism for POLE-related disease than truncating variation. Details ▾Hide ▴
Evidence considered
  • Local POLE framework is built around missense hotspot and in silico rules
Sources
final_classification_framework
BP3 N/AThis is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
BP6 N/AAssertion-only benign evidence was not used, and no benign ClinVar submission was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar entries are uncertain significance
  • not benign
Sources
clinvar ↗
BP7 N/ABP7 does not apply because this is not a synonymous or intronic variant, although SpliceAI does not predict a significant splice effect. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • SpliceAI max delta 0.01
Sources
spliceai ↗

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.2137G>A
Protein (HGVS p.)
NP_006222.2:p.(Glu713Lys)
GRCh38
chr12:132668392 C>T
GRCh37
chr12:133244978 C>T
ClinVar
473514
COSMIC
COSV106057460

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…
gnomAD v4.1 5 / 1,608,750 alleles AF 3.11e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1 2 / 247,784 alleles AF 8.07e-06 · 0 homozygotes · FAF 2.96e-06
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,608,750 alleles · 0 hom · FAF 1.2e-06
European (non-Finnish)5 / 1,177,198 4.2e-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.

gnomAD v2.1

AF 8.1e-06 · 2 / 247,784 alleles · 0 hom · FAF 3e-06
European (non-Finnish)2 / 112,228 1.8e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.108e-06; MAF= 0.00031%, 5/1608750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24737e-06; MAF= 0.00042%, 5/1177198 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.07155e-06; MAF= 0.00081%, 2/247784 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.78209e-05; MAF= 0.00178%, 2/112228 alleles, homozygotes = 0); grpmax FAF= 2.96e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +35 bp
0.010
SpliceAI acceptor gainat +104 bp
0.000
SpliceAI donor lossat +202 bp
0.000
SpliceAI donor gainat +248 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.246
BayesDel
-0.034

How the predictions were used

PP3 Under the local POLE framework, PP3 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a 'likely disease causing' REVEL class and no more than one benign in silico result. This variant was not identified in those tables. In the generic computational review, REVEL is 0.246, BayesDel is -0.033673, and SpliceAI max delta score is 0.01, which do not provide a strong damaging computational signal. Details ▾Hide ▴
Rule
POLE local custom PP3 rule with generic computational fallback
Evidence considered
  • Exact variant not found in Supplementary Tables S2 or S3
  • REVEL 0.246
  • BayesDel -0.033673
  • SpliceAI max delta 0.01
Still missing
  • No qualifying POLE table-based PP3 evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004revelbayesdelspliceai ↗
BP4 Under the local POLE framework, BP4 requires the exact missense variant to appear in the reviewed supplementary in silico tables with a benign-leaning REVEL class and at least four benign in silico results. This variant was not identified in those tables. In the generic computational review, SpliceAI predicts no significant splice impact (max delta 0.01), but REVEL 0.246 and BayesDel -0.033673 do not by themselves provide sufficiently validated benign missense evidence to apply BP4. Details ▾Hide ▴
Rule
POLE local custom BP4 rule with generic computational fallback
Evidence considered
  • Exact variant not found in Supplementary Tables S2 or S3
  • SpliceAI max delta 0.01
  • REVEL 0.246
  • BayesDel -0.033673
Still missing
  • No qualifying POLE table-based BP4 evidence for this exact variant was identified
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗revelbayesdel
BP7 N/ABP7 does not apply because this is not a synonymous or intronic variant, although SpliceAI does not predict a significant splice effect. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • SpliceAI max delta 0.01
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.246. BayesDel score = -0.033673.

2 paper records 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

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 5 / 1,608,750 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 2 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

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= 3.108e-06; MAF= 0.00031%, 5/1608750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24737e-06; MAF= 0.00042%, 5/1177198 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.07155e-06; MAF= 0.00081%, 2/247784 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.78209e-05; MAF= 0.00178%, 2/112228 alleles, homozygotes = 0); grpmax FAF= 2.96e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 473514)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.246. BayesDel score = -0.033673.

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; COSV106057460, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.