Classification rationale

PM2 VUS

POLE c.1718G>A

The POLE c.1718G>A (p.Arg573Gln) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar as uncertain significance by 3 clinical laboratories.¹ This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles), which remains below the 0.1% PM2 rarity threshold.² p.Arg573Gln is not listed among the recurrent POLE exonuclease-domain variants in León-Castillo et al. Supplementary Table S1 and was not identified in the Cancer Hotspots review, which does not support PM1 or the POLE-specific PS4 recurrence rule.³ Available computational evidence does not support a protein-damaging or benign in silico assignment because this exact variant is not listed in the POLE supplementary in silico tables, REVEL is 0.228, and SpliceAI shows a possible splice impact with a max delta score of 0.20.⁴

PM2 → VUS

1 output/evidence.json:results.cosmicoutput/case_summary.json:compact_evidence.clinvar

2 output/evidence.json:results.gnomad.GNOMAD_V2_1output/evidence.json:results.gnomad.GNOMAD_V4_1

3 vcep_db/POLE/files/PATH-250-323-s002.xlsxoutput/evidence.json:results.hotspotsoutput/final_classification_framework.json

4 vcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxoutput/evidence.json:results.reveloutput/evidence.json:results.spliceai

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 · 21 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 review Pathogenic

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles) in Middle Eastern individuals. These values are below the project's default PM2 rarity threshold of 0.1%, supporting PM2.

gnomAD v2.1: absentgnomAD v4.1 total AF=1.85855e-06gnomAD v4.1 highest population AF=0.000165017

Assessed · not applied · 6 not met · 15 not assessed

Pathogenic

PS1 No evidence was identified showing that a different nucleotide change causes the same p.Arg573Gln amino acid substitution and has already been established as pathogenic or likely pathogenic, so PS1 cannot be assessed from the available data.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified, so PS2 cannot be applied.

PS3 No well-established functional studies demonstrating a damaging effect of p.Arg573Gln were identified, so PS3 cannot be applied.

PS4 The local POLE framework applies PS4 only to exact recurrent exonuclease-domain variants that are present in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic set.

PM1 The local POLE framework restricts PM1 to specific exact exonuclease-domain hotspot or recurrent pathogenic substitutions from León-Castillo et al.

PM3 No evidence was identified showing this variant in trans with another pathogenic variant in a recessive disorder context, so PM3 cannot be assessed.

PM5 No pathogenic or likely pathogenic missense comparison variant at the same amino acid residue was identified in the available evidence, so PM5 cannot be assessed.

PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be applied.

PP1 No segregation data were identified to show that this variant tracks with disease in affected family members, so PP1 cannot be assessed.

PP2 No gene-specific evidence was retrieved to show that pathogenic POLE variation is predominantly missense with a low rate of benign missense variation, so PP2 cannot be assessed from the available data.

PP3 The local POLE framework applies PP3 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result.

PP4 No phenotype or family history data specific enough to establish a highly specific POLE-related clinical presentation were identified, so PP4 cannot be assessed.

Benign

BA1 The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BA1 threshold of 1%.

BS1 The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BS1 threshold of 0.3%.

BS2 No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2, so the criterion cannot be assessed.

BS3 No well-established functional studies demonstrating no damaging effect of p.Arg573Gln were identified, so BS3 cannot be applied.

BS4 No segregation evidence showing lack of cosegregation with disease was identified, so BS4 cannot be assessed.

BP1 No gene-specific evidence was retrieved showing that POLE disease is primarily caused by truncating variants with missense variants rarely pathogenic, so BP1 cannot be assessed.

BP2 No phase data or co-occurrence evidence with another pathogenic variant were identified, so BP2 cannot be assessed.

BP4 The local POLE framework applies BP4 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely benign and at least four benign in silico results.

BP5 No evidence was identified showing an alternate molecular cause that fully explains the phenotype, so BP5 cannot be assessed.

N/A · 6 PVS1 · PM4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85855e-06; MAF= 0.00019%, 3/1614158 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,158
0 hom

Middle Eastern 1 / 6,060	0.017%
Admixed American 1 / 60,010	0.0017%
Remaining individuals 1 / 62,512	0.0016%

+ 7 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).

SpliceAI ↗

Functional 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 ↗

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 ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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