Classification rationale

PM2 BP4 VUS

POLE c.5066C>T missense · exon 38

PM2 (Supporting): absent from gnomAD v2.1, v4.1 (0 of 1,608,632 alleles), and gnomAD-Canada v1.0. BP4 (Supporting): REVEL score 0.178 is below the 0.250 benign threshold. VUS: PM2_Supporting plus BP4_Supporting meets no pathogenic or benign combination rule under the local POLE framework.

PM2 + BP4 → VUS

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 25 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 · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v2.1 and v4.1 (allele count 0 of 1,608,632, AF 0.0) and from gnomAD-Canada v1.0.

gnomAD v4.1: exact variant 12-132642284-G-A; total AC 0, total AN 1,608,632, AF 0.0, homozygotes 0; the highest-observed listed subpopulation is AFR with AC 0/AN 74,784 and AF 0.0.gnomAD v2.1 reports the exact variant as absent.gnomAD-Canada v1.0 reports the exact variant as absent.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): REVEL score 0.178 is below the 0.250 BP4 threshold.

The POLE local BP4 rule requires an exact Supplementary Table S2 or S3 entry classified as 'Likely benign' or 'Likely-benign' with at least four benign in silico results; p.Thr1689Ile is not listed in either table, so the framework directs generic fallback.The generic missense fallback assigns BP4_Supporting for REVEL <0.250; the observed REVEL score is 0.178. The use of calibrated REVEL computational thresholds is supported by Pejaver et al. (PMID:36413997).BayesDel score -0.338929 was not used because no verified published BayesDel threshold is available for this pipeline.

Assessed · not applied · 11 not met · 14 not assessed

Pathogenic

PVS1 Not met: this is a missense substitution, p.(Thr1689Ile), not a predicted null (nonsense, frameshift, or splice-site) variant.

PS1 Not assessed: no verified pathogenic variant producing the same p.Thr1689Ile change was available; ClinVar's sole submission is uncertain significance.

PS2 Not assessed: no de novo assertion, parental genotypes, or maternity/paternity confirmation was documented.

PS3 Not assessed: no variant-specific validated functional assay result for p.Thr1689Ile was available.

PS4 Not met: p.Thr1689Ile is not among the four exonuclease-domain variants the POLE framework qualifies for PS4, and no COSMIC record exists.

PM1 Not met: p.Thr1689Ile is not a listed exonuclease-domain hotspot, and no statistically significant hotspot at Thr1689 was reported.

PM3 Not assessed: no confirmed in-trans pathogenic comparator, phase information, or biallelic disease evidence was available.

PM4 Not met: a single amino-acid substitution with no in-frame insertion/deletion or protein-length alteration.

PM5 Not assessed: no verified same-residue comparator variant at Thr1689 was identified.

PM6 Not assessed: no de novo observation with confirmed maternity and paternity was documented.

PP1 Not assessed: no segregation data, informative meioses, or relative genotype information was available.

PP2 Not assessed: no POLE-specific data showing pathogenic missense predominates with a low benign missense rate.

PP3 Not met: REVEL score 0.178 is below the PP3 threshold and instead meets BP4.

PP4 Not assessed: no proband or tumor phenotype indicating a POLE-related disorder was supplied.

PP5 Not met: ClinVar has only one uncertain-significance submission and no expert-panel pathogenic assertion for this exact variant.

Benign

BA1 Not met: gnomAD v4.1 allele frequency is 0.00000% versus the >5% stand-alone benign threshold.

BS1 Not met: absent from all gnomAD datasets, with no allele frequency above the maximum credible population frequency.

BS2 Not met: no healthy adult carriers documented; gnomAD reports 0 homozygotes.

BS3 Not assessed: no validated benign functional assay evidence for p.Thr1689Ile was available.

BS4 Not assessed: no unaffected relatives tested or informative non-segregation analysis documented.

BP1 Not assessed: no POLE-specific rule establishing that missense variants are generally tolerated.

BP2 Not assessed: no in-trans observation with a pathogenic variant or phase information was available.

BP3 Not met: missense substitution produces no in-frame protein-length change.

BP5 Not assessed: no individual phenotype or alternate molecular diagnosis was supplied.

BP6 Not met: no ClinVar expert-panel benign assertion exists; the sole submission is uncertain significance.

N/A · 1 BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1608632 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74784 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,608,632
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 (1 clinical laboratory). (ClinVarID = 2576435)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.178. BayesDel score = -0.338929.

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 · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots