Classification rationale

PM2 VUS

POLE c.889T>C

POLE p.(Ser297Pro) is absent from gnomAD v2.1.¹ The variant is also absent from gnomAD v4.1, supporting rarity, although no explicit POLE-specific population cutoff was retrieved.² SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, but no explicit computational threshold framework was retrieved to convert the available in silico data into PP3 or BP4.³ No ClinVar classification has been reported for this variant.⁴ With PM2 applied and no additional pathogenic or benign criteria established, this variant is classified as a variant of uncertain significance under the retrieved generic ACMG/AMP combination rules.⁵

PM2 → VUS

1 gnomad_v2 ↗

2 gnomad_v4 ↗

3 spliceai ↗

4 clinvar ↗

5 generic_acmg_combination_rules

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 · 24 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 review Pathogenic

The variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity. No explicit POLE-specific PM2 frequency cutoff was retrieved, so this is a generic ACMG rarity assessment.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 20 not assessed

Pathogenic

PS1 No retrieved source established that this amino-acid change matches a previously classified pathogenic variant at the same residue with the same protein consequence.

PS2 No de novo data were retrieved.

PS3 No well-established functional assay data were retrieved for this variant.

PS4 No case-control enrichment or multiple independent affected observations were retrieved.

PM1 This residue was not identified as a statistically significant hotspot, and no critical functional domain evidence meeting PM1 was retrieved.

PM3 No phase data or occurrence with another pathogenic allele were retrieved.

PM5 No different pathogenic missense change at codon 297 was retrieved.

PM6 No assumed de novo data without parental confirmation were retrieved.

PP1 No segregation data were retrieved.

PP2 No retrieved gene-level evidence established that missense variation is a predominant disease mechanism suitable for PP2 application.

PP3 REVEL is 0.774 and SpliceAI maximum delta score is 0.00, but no explicit computational threshold framework applicable to this case was retrieved to convert these values into PP3.

PP4 No phenotype-specific evidence for a highly specific POLE-associated presentation was provided.

PP5 No reputable external pathogenic classification was retrieved.

Benign

BA1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet a stand-alone benign population frequency criterion.

BS1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet a benign strong population frequency criterion.

BS2 No observations in healthy adult individuals inconsistent with disease penetrance were retrieved.

BS3 No well-established functional evidence demonstrating no damaging effect was retrieved.

BS4 No lack-of-segregation data were retrieved.

BP1 No retrieved gene-level evidence supported BP1 for this missense variant.

BP2 No phase data with another pathogenic variant were retrieved.

BP3 No evidence was retrieved that the variant lies in a repetitive region without known function.

BP4 Benign computational evidence was not established.

BP5 No alternate molecular explanation accounting for the phenotype was retrieved.

BP6 No reputable benign classification was retrieved.

N/A · 3 PVS1 · PM4 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional

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 ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

5Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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