POLE

Final classification

VUS

POLE c.1708C>A · p.Leu570Met

POLE

NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain.

Gene

POLE

Transcript

NM_006231.4

HGVS · transcript:coding

NM_006231.4:c.1708C>A

Consequence

N/A

GRCh38

chr12:132672301 G>T

GRCh37

chr12:133248887 G>T

Basis The León-Castillo et al. 2020 custom POLE framework (gene_framework) was applied. Only one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. No pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied. Per the framework (which mirrors generic ACMG/AMP 2015 combination logic), all other combinations default to Uncertain Significance. ▾

The León-Castillo et al. 2020 custom POLE framework (gene_framework) was applied. Only one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. No pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied. Per the framework (which mirrors generic ACMG/AMP 2015 combination logic), all other combinations default to Uncertain Significance.

Classification rationale

PM2 BP4 VUS

POLE c.1708C>A

NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain. The variant is absent from gnomAD v2.1 (exomes) and v4.1 (exomes) population databases, meeting PM2 at moderate strength (PM2_Moderate).¹ Multiple in silico tools predict a benign impact: REVEL score 0.267 (benign-leaning, below the 0.5 pathogenic threshold), BayesDel score -0.221 (benign), and SpliceAI max delta 0.06 (no splice impact). This meets BP4 at supporting benign strength (BP4_Supporting).² The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories (Variation ID 405767). It is not among the established POLE exonuclease-domain hotspot mutations identified by León-Castillo et al. 2020, and is absent from COSMIC and Cancer Hotspots.³ With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. The variant is classified as Variant of Uncertain Significance (VUS) under the León-Castillo et al. 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗vcep_path_250_323_s002

4 final_classification_frameworkgeneric_acmg_combination_rules

Gene diagram · NM_006231.4 · variants mapped to exon structure

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

“

Absent from gnomAD v4.1.

“

Absent from gnomAD v2.1.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 405767)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.267. BayesDel score = -0.220802.

SpliceAI ↗

Functional 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 ↗

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.

COSMIC ↗ Hotspots ↗

Literature · 3 PMIDs triaged · 2 high-priority

3papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

25741868 ↗ functional

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

25394175 ↗ case observation

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PP5PS4

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots