Classification rationale

PM2 VUS

POLE c.2284C>T

PM2 (Supporting): gnomAD allele frequency 0.0008% (v2.1) and 0.00043% (v4.1) with zero homozygotes, well below the 0.1% population-frequency threshold. With only PM2 (Supporting) met, no ACMG/AMP 2015 pathogenic, likely-pathogenic, or benign combination is satisfied, yielding Uncertain Significance (VUS).

PM2 → VUS

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): gnomAD allele frequency 0.0008% (v2.1) and 0.00043% (v4.1) with zero homozygotes, below the 0.1% PM2 threshold.

gnomAD v2.1 AF 7.95469e-06 (0.0008%, 2/251,424, 0 homozygotes) - below the PM2 threshold of AF <0.1% for non-VCEP gnomAD (maximum credible AF framework, Whiffin et al. 2017, PMID 28518168; PM2 'absent/extremely low frequency' definition, Richards et al. 2015, PMID 25741868)gnomAD v4.1 AF 4.33737e-06 (0.00043%, 7/1,613,882, 0 homozygotes), grpmax FAF 1.83e-06 (0.00018%) - below the PM2 threshold of AF <0.1% (Whiffin et al. 2017, PMID 28518168; Richards et al. 2015, PMID 25741868)PM2 applied at Supporting strength per ClinGen SVI general recommendation weighting PM2 as supporting evidence, consistent with the Bayesian calibration of ACMG/AMP criterion weights (Tavtigian et al. 2018, PMID 29565419)

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied

Pathogenic

PS1 Not met: no source establishes any Arg762 substitution as pathogenic, and no alternative nucleotide change at this codon produces Trp.

PS2 Not assessed: no proband-parent trio or de novo occurrence data were available.

PS3 Not assessed: no functional assay evidence for this variant was available.

PS4 Not met: the variant is absent from the framework's recurrent-variant table and has only a single somatic COSMIC occurrence (n=1), which is not recurrence.

PM1 Not met: Arg762 lies outside the framework's exonuclease-domain hotspot region (residues 286-459) and in none of its hotspot lists.

PM3 Not assessed: no phase, pedigree, or proband genotype data were available to evaluate a trans arrangement.

PM5 Not assessed: no pathogenic comparator missense at Arg762 was identified; the required same-residue survey is pending human review.

PM6 Not assessed: no evidence of a de novo occurrence, with or without confirmed parentage, was available.

PP1 Not assessed: no family segregation data were available.

PP2 Not assessed: no gene-level missense constraint metric (e.g., gnomAD Z-score) was available to establish a low rate of benign missense variation.

PP3 Not met: REVEL 0.552 falls in the indeterminate range (PP3 requires >=0.932), and SpliceAI max delta 0.00 shows no splice impact.

PP4 Not assessed: no proband phenotype or family-history data were available to establish phenotype specificity.

PP5 Not met: ClinVar lists only Uncertain significance from three clinical laboratories, with no expert-panel pathogenic classification.

Benign

BA1 Not met: the highest observed allele frequency is 0.00327%, versus the >1% BA1 threshold.

BS1 Not met: the highest allele frequency, 0.00327%, is about 100-fold below the >0.3% BS1 threshold.

BS2 Not met: no homozygotes and only 7 ultra-rare heterozygous carriers in 1.6 million gnomAD alleles, contrary to BS2's expected healthy-adult enrichment.

BS3 Not assessed: no functional assay evidence showing a lack of damaging effect was available.

BS4 Not assessed: no segregation data were available to test for lack of segregation in affected family members.

BP1 Not met: POLE disease is driven by missense rather than truncating variants, so a missense change cannot receive BP1.

BP2 Not assessed: no phase data relative to another variant were available.

BP4 Not met: REVEL 0.552 is far above the <=0.016 BP4 threshold, and SpliceAI shows no splice impact.

BP5 Not assessed: no case-level data on an alternate molecular basis of disease were available.

BP6 Not met: no expert-panel Benign/Likely benign classification exists; ClinVar shows only Uncertain significance.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.33737e-06; MAF= 0.00043%, 7/1613882 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09806e-05; MAF= 0.00110%, 1/91070 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.95469e-06; MAF= 0.00080%, 2/251424 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00043% · 7 / 1,613,882
0 hom · FAF 0.00018%

South Asian 1 / 91,070	0.0011%
European (non-Finnish) 6 / 1,179,976	0.00051%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0008% · 2 / 251,424
0 hom

South Asian 1 / 30,616	0.0033%
European (non-Finnish) 1 / 113,704	0.00088%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

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 (3 clinical laboratories). (ClinVarID = 420873)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.552. BayesDel score = 0.0522946.

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; COSV57690452, n = 1 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 · 2 PMIDs not cited in assessment

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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR