Classification rationale

VUS

POLE c.4307G>A missense · exon 34

For p.Arg1436Gln (NM_006231.4:c.4307G>A), the governing POLE material records one somatic COSMIC occurrence but does not place the variant among the exact pathogenic hotspot or non-hotspot PM1 substitutions. The variant is not supported by PS1, PM1, PM5, PP2, or BP1 on the reviewed evidence; PM5, PP2, and BP1 remain not assessed where the required validated comparator or gene-level calibration is unavailable. No segregation or de novo criterion is met from the available evidence. A ClinVar submission signal mentioning an unaffected brother is insufficiently documented to establish BS4.

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 · 0 applied · 23 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 · 0

No criteria were applied for this variant.

Assessed · not applied · 10 not met · 13 not assessed

Pathogenic

PS1 Not met: no established pathogenic POLE variant producing the same Arg1436Gln amino-acid change was identified.

PS2 Not assessed: no documented proband-parent testing or confirmed de novo observation is available for the POLE c4307G>A variant.

PS3 Not assessed: no validated variant-specific functional assay is available, and computational predictions were explicitly unconfirmed by functional testing.

PS4 Not met: the exact variant appears once overall in Table S1 (COSMIC 1, TCGA 0), below the governing recurrence definition of at least two combined cases.

PM1 Not met: p.R1436Q is absent from POLE's exact PM1 variant lists and is not identified as an approved critical-domain variant.

PM2 Not met: gnomAD v4.1 group-maximum frequency is 0.00012744, exceeding the PM2 threshold of 0.0001 despite an overall frequency of 3.34575e-05.

PM5 Not assessed: no established pathogenic alternate substitution at POLE residue 1436 was available for comparison.

PM6 Not assessed: no affected-proband report or presumed de novo observation is documented for the POLE c4307G>A variant.

PP1 Not assessed: no affected relatives, informative meioses, pedigree, or segregation results are documented for the POLE c4307G>A variant.

PP2 Not assessed: no validated POLE-specific evidence establishes the missense-mechanism pattern required for PP2.

PP3 Not met: REVEL 0.42 is below the generic PP3 threshold of 0.644, and POLE Table S3 classifies R1436Q as Likely-benign.

PP4 Not assessed: no case-specific, highly specific POLE phenotype is documented for comparison with the variant's associated disorders.

PP5 Not met: ClinVar has zero expert-panel submissions for the exact variant and no expert-panel Pathogenic or Likely pathogenic classification.

Benign

BA1 Not met: gnomAD v4.1 highest population frequency is 0.000216652, far below the BA1 threshold of 0.05.

BS1 Not met: gnomAD v4.1 highest population frequency is 0.000216652, below the BS1 threshold of 0.01.

BS2 Not assessed: gnomAD v4.1 reports zero homozygotes, but provides no phenotype-confirmed healthy-carrier evidence for BS2.

BS3 Not assessed: no validated variant-specific functional assay demonstrates a normal effect, and no benign assay threshold or control data are available.

BS4 Not assessed: a ClinVar signal mentions an unaffected brother, but lacks verifiable family genotypes, phenotype assessment, and segregation methodology.

BP1 Not assessed: no validated POLE-specific evidence shows that disease is caused mainly by non-missense variants.

BP2 Not assessed: no affected-proband co-occurrence, second pathogenic variant, or cis/trans phase result is documented for this variant.

BP4 Not met: REVEL 0.42 exceeds the generic BP4 threshold of 0.29, and POLE Table S3 reports only one benign in-silico result.

BP5 Not assessed: no validated alternative molecular diagnosis or co-occurrence evidence is documented to explain the relevant phenotype.

BP6 Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification, despite one ordinary Likely benign submission.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.34575e-05; MAF= 0.00335%, 54/1613988 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000216652; MAF= 0.02167%, 13/60004 alleles, homozygotes = 0); grpmax FAF= 0.00012744.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.35974e-05; MAF= 0.00836%, 21/251204 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000202406; MAF= 0.02024%, 7/34584 alleles, homozygotes = 0); grpmax FAF= 9.474e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0033% · 54 / 1,613,988
0 hom · FAF 0.013%

Admixed American 13 / 60,004	0.022%
Remaining individuals 13 / 62,490	0.021%
East Asian 1 / 44,878	0.0022%
European (non-Finnish) 26 / 1,180,030	0.0022%
African/African American 1 / 74,930	0.0013%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0084% · 21 / 251,204
0 hom · FAF 0.0095%

Admixed American 7 / 34,584	0.02%
Remaining individuals 1 / 6,126	0.016%
European (non-Finnish) 12 / 113,518	0.011%
Ashkenazi Jewish 1 / 10,070	0.0099%

+ 4 not observed (African/African American, East Asian, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 473660)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.61). REVEL score = 0.42. BayesDel score = 0.085235.

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 previously been reported in somatic cancers (COSMIC; COSV57674115, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

25741868 ↗ 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. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

25394175 ↗ 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. CLINVAR

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