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LYFE SCIENCES
Project: HERA
NM_006231.4:c.2083T>C
p.Phe695Leu  ·  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.2083T>C (p.Phe695Leu; p.F695L) variant has not been identified as a recurrent POLE hotspot in the León-Castillo endometrial carcinoma datasets or Cancer Hotspots and has been reported in ClinVar mainly as uncertain significance, with some likely benign submissions.

hotspots ↗ clinvar ↗
2

This variant is rare in population databases, with an allele frequency of 0.00320% in gnomAD v2.1 and 0.00329% in gnomAD v4.1, both below the project's 0.1% PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact (maximum delta score 0.08), REVEL is 0.322, and BayesDel is -0.367686.

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= 3.19909e-05; MAF= 0.00320%, 9/281330 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139626; MAF= 0.01396%, 1/7162 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.28709e-05; MAF= 0.00329%, 53/1612366 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164636; MAF= 0.01646%, 1/6074 alleles, homozygotes = 0); grpmax FAF= 9.22e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (2 clinical laboratories).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
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
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.322. BayesDel score = -0.367686.
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.
ResidueF695
Hotspots ↗