Genetic Information

Gene & Transcript Details

Gene
POLE
Transcript
NM_006231.4 MANE Select
Total Exons
—
Reference Sequence
NC_000012.11
Alternative Transcripts
IDStatusDetails
NM_006231.4 MANE Select 7823 nt | 28–6888
NM_006231.2 Alternative 7859 nt | 45–6905
NM_006231.3 RefSeq Select 8024 nt | 210–7070

Variant Details

HGVS Notation
NM_006231.4:c.2083T>C
Protein Change
F695L
Location
Exon 19 (Exon 19 of )
19
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.0032 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Uncertain Significance (VUS)
2 publications
Publications List
PMID: 35534704

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 695 of the POLE protein (p.Phe695Leu). This variant is present in population databases (rs5744799, gnomAD 0.008%). This missense change has been observed in individual(s) with personal or family history of POLE-related conditions (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 240419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Clinical Statement

"This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (2 clinical laboratories)."

COSMIC Somatic Evidence

Open
COSMIC ID
Recurrence
0 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene POLE.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: POLEF695LPOLEF695LSomaticNCBI Gene:5426|Show additional gene information Variant OverviewPOLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high mutation rates, most frequently in endometrial and colorectal cancer.The POLE F695L mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Mixed/VUS
PP3 Applied
No
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.08 -19 bp
- Donor Loss (DL) 0.0 148 bp
+ Acceptor Gain (AG) 0.0 50 bp
+ Donor Gain (DG) 0.0 144 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

BP4

BP4 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)