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.1 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.2 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 PS4.3 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).4
Final classification
VUS
PM2
POLE
c.2044G>A
p.Glu682Lys
This variant
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.
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.
Classification rationale
PM2
VUS
POLE c.2044G>A
PM2
→
VUS
1
vcep_path_250_323_s002clinvar ↗
3
final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002
4
vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗
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.
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 23 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
moderate
Pathogenic
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.
gnomAD v2.1 AF 4.16264e-061/240232 alleles0 homozygotes.
Assessed · not applied
· 4 not met · 19 not assessed
Pathogenic
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.
PS2
No confirmed de novo data were identified for this variant, so PS2 was not assessed.
PS3
No well-established functional studies demonstrating a damaging effect of p.Glu682Lys were identified, so PS3 was not assessed.
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.
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.
PM3
No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting, so PM3 was not assessed.
PM5
No evidence was identified showing a different pathogenic missense change at codon 682 that would support PM5, so PM5 was not assessed.
PM6
No assumed de novo data were identified for this variant, so PM6 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
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.
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.
PP4
No phenotype information was provided that was sufficiently specific for a POLE-related disorder, so PP4 was not assessed.
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.
Benign
BA1
This variant does not meet the BA1 population threshold.
BS1
This variant does not meet the BS1 population threshold.
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.
BS3
No well-established functional studies showing no damaging effect of p.Glu682Lys were identified, so BS3 was not assessed.
BS4
No segregation studies showing lack of cosegregation with disease were identified, so BS4 was not assessed.
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.
BP2
No phase information or co-occurrence data were identified to support BP2, so BP2 was not assessed.
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.
BP5
No case-level evidence was identified showing an alternate molecular explanation for the observed phenotype, so BP5 was not assessed.
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.
N/A · 4
PVS1 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,600,942
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
South Asian 1 / 89,100 |
0.0011% |
European (non-Finnish) 2 / 1,172,782 |
0.00017% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00042%
· 1 / 240,232
0 hom
0 hom
East Asian 1 / 18,120 |
0.0055% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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
Unknown Oncogenic Effect
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
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links