Classification rationale

PM2PP2 BP4 VUS

POLE c.6634A>G missense · exon 47

PM2 supporting: gnomAD v4.1 total allele frequency 1.23936e-06 (2/1,613,730 alleles) sits far below the 0.0001 rarity threshold. PP2 supporting: POLE pathogenicity is driven by exonuclease-domain missense substitutions, so missense is an established disease mechanism for this gene. BP4 supporting: REVEL 0.212 falls in the benign computational band (<=0.29) for this missense substitution. VUS: two supporting pathogenic criteria (PM2, PP2) conflict with one supporting benign criterion (BP4), and no combination rule reaches Likely Pathogenic or Likely Benign.

PM2 + PP2 + BP4 → VUS

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 · 3 applied · 20 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 · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting: gnomAD v4.1 total allele frequency 1.24e-06 versus the 0.0001 PM2 supporting rarity threshold.

PM2 threshold applied from the supplied published calibration: supporting pathogenic strength when the variant is absent or at an allele/filtering frequency <= 0.0001 in a large control population (ACMG/AMP 2015, PMID:25741868; ClinGen SVI recommendation to downgrade PM2 to supporting).gnomAD v4.1 (all-comers totals; default source): variant chr12-132625668-T-C, total AF 1.23936e-06 (AC 2 / AN 1,613,730), homozygotes 0; grpmax FAF 2.8e-07; highest ancestry European (non-Finnish) AF 1.69488e-06 (AC 2 / AN 1,180,028), homozygotes 0; exome AF 1.3686e-06 (2/1,461,430), genome AF 0 (0/148,300).gnomAD v2.1 (all-comers totals; default source): variant 12-133202254-T-C, reported absent from gnomAD v2.1.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP2 supporting Pathogenic

Met at supporting: POLE pathogenicity is driven by exonuclease-domain missense substitutions, so missense is an established disease mechanism for this gene.

León-Castillo et al. 2020 (J Pathol 250:323-335): all five pathogenic, recurrent 'hotspot' POLE exonuclease-domain mutations (P286R, V411L, S297F, A456P, S459F) are missense substitutions, establishing missense as the pathogenic mechanism in POLE.Supplementary Table S2 (PATH-250-323-s003) tabulates missense POLE variants by in silico tool class, consistent with missense being the relevant variant class for POLE pathogenicity review.Gene context: POLE encodes the catalytic subunit of DNA polymerase epsilon; germline mutations cause polyposis and colorectal cancer predisposition, and the characterised disease alleles are proofreading-domain missense changes.

BP4 supporting Benign

Met at supporting: REVEL 0.212 falls in the ClinGen SVI BP4 band (<=0.29) but above the moderate cut-off (<=0.183).

REVEL v1.3 local lookup (source_registry key 'revel') returned score 0.212 for chr12:132625668 T>C (NM_006231.4:c.6634A>G); this is the only predictor used for BP4, per the missense-path rule.ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997): BP4 supporting <=0.29, moderate <=0.183, strong <=0.016. 0.212 is <=0.29 but >0.183, so BP4 is met at Supporting strength.The labeled gray/indeterminate REVEL zone (>0.29 and <0.644) does not contain 0.212, so BP4 is not blocked by a gray-zone score.

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

Pathogenic

PS1 Not met: no established pathogenic source reports the same p.Met2212Val change; ClinVar lists it only once as Uncertain significance.

PS2 Not assessed: no proband, pedigree, or parental genotype data exist to confirm or exclude a de novo occurrence.

PS3 Not assessed: no functional assay of POLE p.Met2212Val exists; the only 'functional' data are in-silico predictor outputs.

PS4 Not met: c.6634A>G (p.Met2212Val) has no row in Supplementary Table S1 and no COSMIC record, failing the >=10 EC-count PS4_Supporting rule.

PM1 Not met: residue 2212 lies outside POLE's exonuclease domain and is absent from the five established hotspots (P286R, V411L, S297F, A456P, S459F).

PM3 Not assessed: no phased POLE genotype, no trans partner, and zero homozygotes in gnomAD v4.1 (2/1,613,730 alleles) leave the in-trans configuration untested.

PM5 Not met: no pathogenic missense variant is reported at residue M2212 (0 same-residue candidates; the ClinVar entry is Uncertain significance).

PM6 Not assessed: no affected proband or any parental testing is documented, so an assumed de novo occurrence cannot be established.

PP1 Not assessed: no pedigree or genotyped family members exist, so there are no meioses available to assess co-segregation.

PP3 Not met: REVEL 0.212 sits below the >=0.644 ClinGen SVI supporting PP3 threshold for this missense variant.

PP4 Not assessed: no proband phenotype, HPO terms, or family history were available to judge specificity for POLE-related disease.

PP5 Not met: the only ClinVar record (1478557) is Uncertain significance from a single non-expert submitter, with no expert-panel Pathogenic assertion.

Benign

BA1 Not met: highest observed allele frequency 1.69e-06 (gnomAD v4.1, European non-Finnish) versus the 0.05 BA1 stand-alone threshold.

BS1 Not met: highest observed allele frequency 1.69e-06 versus the 0.01 BS1 strong benign threshold, roughly 6,000-fold below.

BS3 Not assessed: no functional assay of POLE p.Met2212Val exists, so no non-damaging functional result is available for BS3.

BS4 Not assessed: no pedigree or family genotypes exist for this variant, so non-segregation with disease cannot be evaluated.

BP1 Not met: POLE missense variants are an established pathogenic mechanism, so the gene is not a truncating-only (loss-of-function) disease gene.

BP2 Not assessed: no co-occurring pathogenic POLE allele or phase data, with zero homozygotes in gnomAD v4.1 (2/1,613,730 alleles), so no cis/trans configuration is testable.

BP5 Not assessed: no case-level clinical or molecular data were available to determine whether an alternate molecular basis for disease exists.

BP6 Not met: ClinVar 1478557 is Uncertain significance from one non-expert laboratory, not a Benign/Likely benign expert-panel assertion.

N/A · 5 PVS1 · PM4 · BS2 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23936e-06; MAF= 0.00012%, 2/1613730 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69488e-06; MAF= 0.00017%, 2/1180028 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

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

0.00012% · 2 / 1,613,730
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,180,028

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 = 1478557)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.212. BayesDel score = -0.0354284.

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 ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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