NM_006231.3:c.3799G>A

POLE · NP_006222.2:p.(Glu1267Lys) · NM_006231.3

GRCh37: chr12:133226098 C>T · GRCh38: chr12:132649512 C>T

Gene: POLE Transcript: NM_006231.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

POLE

Transcript

NM_006231.3

Protein

NP_006222.2:p.(Glu1267Lys)

gnomAD AF

0.0 (v2.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2_Supporting is met: NM_006231.3:c.3799G>A (p.Glu1267Lys) is absent from gnomAD v2.1 (0/244,852 alleles), v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1%.

BP4_Supporting is met: multiple in silico tools predict a benign effect — REVEL score 0.262, BayesDel score 0.061, and SpliceAI max delta 0.07 (no splice impact).

PVS1 is not applicable: this is a missense variant outside the scope of the ClinGen SVI PVS1 null-variant framework (PMC6185798).

The variant is absent from ClinVar, COSMIC, and cancerhotspots.org. No variant-specific functional data or literature reports were identified.

The León-Castillo et al. 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) were assessed: the variant is not in the exonuclease domain, not recurrent in EC cohorts, and absent from Supplementary Tables S1-S3.

Overall, with only PM2_Supporting and BP4_Supporting met, and all other criteria not met or not applicable, this variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Conflicting pathogenic (PM2_Supporting) and benign (BP4_Supporting) supporting-level evidence, with no very strong, strong, or moderate criteria met, falls outside any Pathogenic/Likely Pathogenic/Benign/Likely Benign combination under standard ACMG/AMP 2015 rules and defaults to VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon deletions). NM_006231.3:c.3799G>A is a missense variant (p.Glu1267Lys) and does not fall into any null-variant bucket under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at c.3799 has been reported as pathogenic. The variant is absent from ClinVar and no literature reports a different pathogenic substitution at this position.	clinvar gnomad_v2
PS2	Not met	No de novo observation has been reported for this variant. No proband genotype data, parental studies, or family trios are available.
PS3	Not met	No variant-specific or range-based functional data exists for p.Glu1267Lys. The variant is absent from COSMIC, OncoKB contains no variant-specific functional evidence, and no publications testing POLE E1267K were identified.	oncokb
PS4	Not met	The León-Castillo custom POLE framework requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10. p.Glu1267Lys is absent from Supplementary Table S1 and absent from COSMIC; no case-control prevalence data are available.	vcep_path_250_323_s002 clinvar
PS5	Not met	No ClinVar entry exists for this variant. No expert panel classification or reputable source has asserted pathogenicity.	clinvar
PM1	Not met	The León-Castillo custom POLE framework restricts PM1 to exonuclease-domain missense variants (residues ~1-471). p.Glu1267Lys is located at residue 1267 in the C-terminal polymerase region, far outside the exonuclease domain. It is not one of the five established pathogenic hotspot mutations (P286R, V411L, S297F, A456P, S459F) and is not recurrent in the EC cohorts; cancerhotspots.org does not identify residue 1267 as a statistically significant hotspot.	vcep_path_250_323_s002 vcep_path_250_323
PM2	Met	This variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (AF < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same codon (1267) was identified. PM5 candidate harvesting found zero same-residue ClinVar candidates, and ClinVar contains no entries at all for this variant or codon.	pm5_candidates clinvar
PM6	Not met	No de novo observation has been reported for this variant. No proband genotype data or parental confirmation studies are available.
PP1	Not met	No co-segregation data are available. No family studies or pedigrees have been reported for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. No missense constraint data (HCI prior, Z-score) are available for POLE to support this criterion. Additionally, the variant lies outside the exonuclease domain where pathogenic missense clustering is well-established.
PP3	Not met	The León-Castillo custom POLE framework PP3 rule requires the variant to be listed in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result; E1267K is absent from both tables. Under generic fallback, REVEL score 0.262 (benign-leaning), BayesDel 0.061 (benign-leaning), and SpliceAI max delta 0.07 (no splice impact) collectively do not support a damaging prediction.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not met	No proband phenotype or clinical data have been provided. The patient's clinical presentation and family history are unknown.
PP5	Not met	This variant is absent from ClinVar. There are no submissions or classifications from any reputable source to support PP5.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 (0/244,852 alleles, AF = 0.000%), absent from gnomAD v4.1, and absent from gnomAD-Canada v1.0. Allele frequency does not exceed the BA1 threshold of >1% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD populations. Allele frequency is 0.000% and does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations exist in gnomAD (0 homozygotes across all populations). The variant has not been observed in a healthy adult homozygous state.	gnomad_v2
BS3	Not met	No well-established in vitro or in vivo functional studies exist showing that p.Glu1267Lys has no damaging effect on protein function or splicing.	oncokb
BS4	Not met	No family segregation data are available. Lack of segregation in affected family members cannot be demonstrated.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. In POLE, established pathogenic missense variants in the exonuclease domain are a recognized disease mechanism (e.g., P286R, V411L), so POLE does not meet the BP1 assumption that missense changes are less likely pathogenic.	vcep_path_250_323
BP2	Not met	No observation of this variant in trans with a pathogenic POLE variant has been reported. No phase data are available.
BP4	Met	The León-Castillo custom POLE framework BP4 rule requires the variant to be in Supplementary Table S2/S3 with REVEL class 'Likely benign' and ≥4 benign in silico results; the variant is absent from the tables, falling back to generic assessment. Multiple lines of computational evidence suggest a benign impact: REVEL score 0.262 (benign-leaning), BayesDel score 0.061 (strongly benign-leaning), and SpliceAI max delta 0.07 (no predicted splice impact). Multiple in silico tools concordantly predict no damaging effect.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not met	No alternate molecular basis for disease has been identified in this case. No additional pathogenic variant in POLE or another gene explaining the phenotype has been reported.
BP6	Not met	This variant is absent from ClinVar. There are no submissions or benign classifications from any reputable source to support BP6.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_006231.3:c.3799G>A is a missense variant (p.Glu1267Lys), not a synonymous substitution.

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