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POLEc.2044G>AUncertain significance
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Variant interpretation report

POLE c.2044G>A, p.(Glu682Lys)

NM_006231.4:c.2044G>A NP_006222.2:p.(Glu682Lys) 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
PM2Moderate
PM2 · moderate

This variant is present at very low frequency in population databases and remains below the project's PM2 threshold of 0.1%: gnomAD v2.1 total AF is 4.16e-06 (1/240232 alleles; 0 homozygotes) and gnomAD v4.1 total AF is 1.87e-06 (3/1600942 alleles; 0 homozygotes). These values support PM2.

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 used as the explicit local gene-specific final-classification framework; this framework retains ACMG/AMP 2015 final category thresholds while customizing selected 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
3 / 1,600,942 alleles

gnomAD v4.1: 3 / 1,600,942 alleles. Recorded AF 1.8739e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.16264e-06; MAF= 0.00042%, 1/240232 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.51876e-05; MAF= 0.00552%, 1/18120 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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
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 · 4 not met · 19 not assessed · 4 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.2044G>A (p.Glu682Lys; p.E682K) variant has not been identified in the León-Castillo recurrent COSMIC/TCGA endometrial carcinoma POLE variant table and has been reported in ClinVar as a variant of uncertain significance.

This variant is present at very low frequency in gnomAD, with AF 4.16e-06 in v2.1 (1/240232 alleles) and AF 1.87e-06 in v4.1 (3/1600942 alleles), which is below the project's PM2 threshold of 0.1% and below benign frequency thresholds.

This missense change is not one of the exact POLE hotspot or recurrent exonuclease-domain substitutions specified by the León-Castillo framework for PM1 or PS4.

Available computational evidence does not establish a POLE-specific deleterious or benign pattern for this exact variant because it was not identified in the León-Castillo supplementary computational tables, and SpliceAI predicts no significant splice impact (max delta score 0.04).

Met · 1

PM2 ModerateThis variant is present at very low frequency in population databases and remains below the project's PM2 threshold of 0.1%: gnomAD v2.1 total AF is 4.16e-06 (1/240232 alleles; 0 homozygotes) and gnomAD v4.1 total AF is 1.87e-06 (3/1600942 alleles; 0 homozygotes). These values support PM2. Details ▾Hide ▴
Rule
Project default PM2 threshold: population frequency <0.1%.
Evidence considered
  • gnomAD v2.1 AF 4.16264e-06
  • 1/240232 alleles
  • 0 homozygotes.
  • gnomAD v4.1 AF 1.87390e-06
  • 3/1600942 alleles
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PS4 The León-Castillo POLE framework applies PS4 only to exact missense variants that recur in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and belong to the established pathogenic set. p.Glu682Lys is not listed in that recurrence table, so PS4 is not met. Details ▾Hide ▴
Rule
Custom POLE PS4_Supporting only for exact recurrent pathogenic EC variants in both COSMIC and TCGA with combined count >=10.
Evidence considered
  • The custom PS4 rule is limited to p.P286R
  • p.V411L
  • p.A456P
  • and p.S297F.
  • p.Glu682Lys/E682K was not identified in Supplementary Table S1.
Sources
final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002
PM1 The León-Castillo POLE framework does not award PM1 for all exonuclease-domain variants and instead restricts PM1 to specific exact hotspot or recurrent pathogenic substitutions. p.Glu682Lys is not one of the exact substitutions specified for PM1_Strong, PM1_Moderate, or PM1_Supporting, so PM1 is not met. Details ▾Hide ▴
Rule
Custom POLE PM1 requires exact variant-level matching to predefined hotspot or recurrent exonuclease-domain substitutions.
Evidence considered
  • PM1_Strong variants: P286R
  • V411L
  • S297F
  • A456P
  • S459F.
  • PM1_Moderate variants: F367S
  • L424I
  • M295R
  • P436R
  • M444K
  • D368Y.
  • PM1_Supporting variants: A465V
  • L424V
  • T278M
  • A428T.
Sources
final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002
BA1 This variant does not meet the BA1 population threshold. The highest observed population frequency is 5.52e-05 in gnomAD v2.1 East Asian alleles (0.00552%), which is well below the BA1 threshold of 1%. Details ▾Hide ▴
Rule
Project default BA1 threshold: population frequency >1%.
Evidence considered
  • Highest observed gnomAD v2.1 subpopulation AF 5.51876e-05 (0.00552%).
  • gnomAD v4.1 total AF 1.87390e-06.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant does not meet the BS1 population threshold. The highest observed population frequency is 5.52e-05 in gnomAD v2.1 East Asian alleles (0.00552%), which is below the BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
Project default BS1 threshold: population frequency >0.3%.
Evidence considered
  • Highest observed gnomAD v2.1 subpopulation AF 5.51876e-05 (0.00552%).
  • gnomAD v4.1 total AF 1.87390e-06.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 19 · no assessment recorded

PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a previously established pathogenic POLE variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
Requires the same amino acid change as an established pathogenic variant.
Still missing
  • No same-amino-acid pathogenic comparator was retrieved for this codon.
PS2 No confirmed de novo data were identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
Requires confirmed de novo occurrence in a patient with the disease and no family history.
Still missing
  • No parental testing or confirmed maternity/paternity information was available.
PS3 No well-established functional studies demonstrating a damaging effect of p.Glu682Lys were identified, so PS3 was not assessed. Details ▾Hide ▴
Rule
Requires well-established functional studies supportive of a damaging effect.
Still missing
  • No variant-specific functional assay results were retrieved.
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting, so PM3 was not assessed. Details ▾Hide ▴
Rule
Requires detection in trans with a pathogenic variant for recessive disease.
Still missing
  • No phase information or recessive case data were available.
PM5 No evidence was identified showing a different pathogenic missense change at codon 682 that would support PM5, so PM5 was not assessed. Details ▾Hide ▴
Rule
Requires a novel missense change at an amino acid residue where a different pathogenic missense change is established.
Still missing
  • No codon-specific pathogenic comparator was retrieved for residue Glu682.
PM6 No assumed de novo data were identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Rule
Requires assumed de novo occurrence without full confirmation.
Still missing
  • No parental testing information was available.
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
Requires cosegregation with disease in multiple affected family members.
Still missing
  • No family cosegregation information was available.
PP2 No retrieved gene-level evidence established that POLE is a gene in which missense variation is a common pathogenic mechanism in a way that supports PP2 for this specific variant, so PP2 was not assessed. Details ▾Hide ▴
Rule
Requires a gene with low benign missense variation and common pathogenic missense mechanism.
Still missing
  • No gene-level missense constraint or validated PP2 framework was retrieved.
PP3 The León-Castillo custom PP3 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result. p.Glu682Lys was not identified in those supplementary tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), so PP3 was not assessed. Details ▾Hide ▴
Rule
Custom POLE PP3 requires exact table presence plus likely disease causing REVEL class and <=1 benign in silico result.
Evidence considered
  • p.Glu682Lys/E682K was not identified in Supplementary Tables S2 or S3.
  • SpliceAI max delta score 0.04.
Still missing
  • No POLE-specific computational table entry was retrieved for p.Glu682Lys.
  • No separately retrieved validated generic missense computational framework was available for this case.
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗
PP4 No phenotype information was provided that was sufficiently specific for a POLE-related disorder, so PP4 was not assessed. Details ▾Hide ▴
Rule
Requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Still missing
  • No individual-level clinical phenotype or tumor signature data were available for correlation.
PP5 ClinVar reports this variant as uncertain significance with criteria provided from a single submitter setting rather than as a concordant pathogenic classification from an expert source, so PP5 was not applied. Details ▾Hide ▴
Rule
Do not use PP5 based on non-expert or uncertain ClinVar assertions.
Evidence considered
  • ClinVar classification: Uncertain significance.
  • Review status: criteria provided
  • single submitter.
Sources
clinvar ↗
BS2 Available population data do not show enough unaffected observations to support BS2, and no homozygotes were observed in gnomAD, so BS2 was not assessed. Details ▾Hide ▴
Rule
Requires observation in healthy adults for a condition expected to be fully penetrant at an early age.
Evidence considered
  • gnomAD v2.1 homozygotes: 0.
  • gnomAD v4.1 homozygotes: 0.
Still missing
  • No well-phenotyped unaffected adult cohort evidence was available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies showing no damaging effect of p.Glu682Lys were identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
Requires well-established functional studies showing no damaging effect.
Still missing
  • No variant-specific benign functional assay results were retrieved.
BS4 No segregation studies showing lack of cosegregation with disease were identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
Requires lack of segregation in affected family members.
Still missing
  • No family segregation data were available.
BP1 No retrieved gene-specific evidence supported using BP1 for POLE, and this missense variant cannot be considered benign solely on variant class, so BP1 was not assessed. Details ▾Hide ▴
Rule
Applies when missense variants occur in a gene where primarily truncating variants cause disease.
Still missing
  • No validated BP1 framework for POLE was retrieved.
BP2 No phase information or co-occurrence data were identified to support BP2, so BP2 was not assessed. Details ▾Hide ▴
Rule
Requires observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
Still missing
  • No in trans/in cis co-occurrence evidence was available.
BP4 The León-Castillo custom BP4 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a likely benign REVEL class and at least four benign in silico results. p.Glu682Lys was not identified in those tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), which alone is not sufficient to apply BP4 for a missense variant, so BP4 was not assessed. Details ▾Hide ▴
Rule
Custom POLE BP4 requires exact table presence plus likely benign REVEL class and >=4 benign in silico results.
Evidence considered
  • p.Glu682Lys/E682K was not identified in Supplementary Tables S2 or S3.
  • SpliceAI max delta score 0.04.
Still missing
  • No POLE-specific computational table entry was retrieved for p.Glu682Lys.
  • No separately retrieved validated generic benign missense computational framework was available for this case.
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗
BP5 No case-level evidence was identified showing an alternate molecular explanation for the observed phenotype, so BP5 was not assessed. Details ▾Hide ▴
Rule
Requires a variant found in a case with an alternate molecular basis for disease.
Still missing
  • No individual-level phenotype and alternate-cause data were available.
BP6 ClinVar does not provide a reputable benign or likely benign classification for this variant; the current ClinVar assertion is uncertain significance, so BP6 was not applied. Details ▾Hide ▴
Rule
Do not use BP6 based on non-expert or uncertain database assertions.
Evidence considered
  • ClinVar classification: Uncertain significance.
  • Review status: criteria provided
  • single submitter.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense change, NM_006231.4:c.2044G>A (p.Glu682Lys), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants; therefore PVS1 is not applicable. Details ▾Hide ▴
Rule
Generic PVS1 framework applies only to qualifying loss-of-function variant classes.
Evidence considered
  • POLE was considered eligible for generic PVS1 fallback at the gene level
  • but this specific variant was assigned to the 'other' bucket and generic PVS1 application was set to false.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
Applies to protein length changes due to in-frame indels or stop-loss variants.
BP3 N/AThis variant is a missense substitution rather than an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Rule
Applies to in-frame indels in repetitive regions without known function.
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applies to synonymous or certain noncoding variants with no predicted splice impact.

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.2044G>A
Protein (HGVS p.)
NP_006222.2:p.(Glu682Lys)
GRCh38
chr12:132668485 C>T
GRCh37
chr12:133245071 C>T

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 3 / 1,600,942 alleles AF 1.87e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1 1 / 240,232 alleles AF 4.16e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,600,942 alleles · 0 hom · FAF 2.8e-07
South Asian1 / 89,100 1.1e-05
European (non-Finnish)2 / 1,172,782 1.7e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4.2e-06 · 1 / 240,232 alleles · 0 hom
East Asian1 / 18,120 5.5e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.8739e-06; MAF= 0.00019%, 3/1600942 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.12233e-05; MAF= 0.00112%, 1/89100 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.16264e-06; MAF= 0.00042%, 1/240232 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.51876e-05; MAF= 0.00552%, 1/18120 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 The León-Castillo custom PP3 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result. p.Glu682Lys was not identified in those supplementary tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), so PP3 was not assessed. Details ▾Hide ▴
Rule
Custom POLE PP3 requires exact table presence plus likely disease causing REVEL class and <=1 benign in silico result.
Evidence considered
  • p.Glu682Lys/E682K was not identified in Supplementary Tables S2 or S3.
  • SpliceAI max delta score 0.04.
Still missing
  • No POLE-specific computational table entry was retrieved for p.Glu682Lys.
  • No separately retrieved validated generic missense computational framework was available for this case.
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗
BP4 The León-Castillo custom BP4 rule applies only when the exact missense variant is present in Supplementary Table S2 or S3 with a likely benign REVEL class and at least four benign in silico results. p.Glu682Lys was not identified in those tables, and SpliceAI predicts no significant splice impact (max delta score 0.04), which alone is not sufficient to apply BP4 for a missense variant, so BP4 was not assessed. Details ▾Hide ▴
Rule
Custom POLE BP4 requires exact table presence plus likely benign REVEL class and >=4 benign in silico results.
Evidence considered
  • p.Glu682Lys/E682K was not identified in Supplementary Tables S2 or S3.
  • SpliceAI max delta score 0.04.
Still missing
  • No POLE-specific computational table entry was retrieved for p.Glu682Lys.
  • No separately retrieved validated generic benign missense computational framework was available for this case.
Sources
final_classification_frameworkvcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applies to synonymous or certain noncoding variants with no predicted splice impact.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.448. BayesDel score = 0.133134.

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 3 / 1,600,942 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

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= 1.8739e-06; MAF= 0.00019%, 3/1600942 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.12233e-05; MAF= 0.00112%, 1/89100 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.16264e-06; MAF= 0.00042%, 1/240232 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.51876e-05; MAF= 0.00552%, 1/18120 alleles, homozygotes = 0).

ClinVar

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

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.448. BayesDel score = 0.133134.

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.