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LYFE SCIENCES
Project: HERA
NM_006231.4:c.2044G>A
p.Glu682Lys  ·  POLE
León-Castillo et al. 2020 custom POLE framework · vleon-castillo-2020-custom-framework-v1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

4

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).

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.448. BayesDel score = 0.133134.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE682
Hotspots ↗