NM_006231.4:c.2778G>C

POLE · NP_006222.2:p.(Glu926Asp) · NM_006231.4

GRCh37: chr12:133238199 C>G · GRCh38: chr12:132661613 C>G

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Glu926Asp)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.4:c.2778G>C (p.Glu926Asp) is a missense variant in exon 24 of POLE, located within the DNA polymerase domain (residues 393-1191). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

The variant is not one of the established exonuclease-domain hotspot mutations (P286R, V411L, S297F, A456P, S459F) and does not appear in the León-Castillo et al. 2020 supplementary recurrence or in silico tables. It does not meet the custom POLE framework criteria for PM1, PS4, PP3, or BP4.

Computational predictions are equivocal: REVEL score of 0.281 is below pathogenic thresholds, BayesDel score of -0.171963 is benign-leaning, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple lines of in silico evidence do not support a deleterious effect (PP3 not met) but also do not convincingly support a benign effect (BP4 not met).

This variant has been reported in ClinVar as Uncertain significance (Variation ID 3225427) by a single clinical laboratory. No variant-specific functional studies, segregation data, or case-control evidence were identified.

The only publication associated with this variant (PMID:25394175) is an ACMG/NSGC practice guideline on cancer predisposition referral indications that does not mention this specific variant and does not provide variant-level evidence (PP5 not met).

With only PM2_Supporting met and no other pathogenic or benign criteria triggered, this variant remains a Variant of Uncertain Significance (VUS) under the León-Castillo 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.

Final determination:

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	Missense variant (NP_006222.2:p.Glu926Asp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice ±1/2); this variant falls into the 'other' bucket under the generic PVS1 decision tree (PMC6185798) and does not trigger PVS1.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence of a different nucleotide change at codon 926 resulting in the same amino acid substitution (p.Glu926Asp) that has been previously classified as pathogenic. No same-amino-acid comparator identified.
PS2	Not assessed	No de novo data available for NM_006231.4:c.2778G>C in any reviewed source. No parental testing or confirmed de novo reports were identified.
PS3	Not assessed	No variant-specific functional studies identified for p.Glu926Asp. OncoKB reports no reviewed functional evidence for this variant. No publications with functional characterization of this exact substitution were found.	oncokb
PS4	Not met	Under León-Castillo 2020 custom POLE framework, PS4_Supporting requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined EC count ≥10. NM_006231.4:c.2778G>C (p.E926D) is absent from Supplementary Table S1. Under generic ACMG/AMP, no case-control data demonstrating enrichment in affected individuals versus controls is available. ClinVar reports a single submitter classifying as VUS, without case-level evidence.	clinvar vcep_path_250_323_s002
PS5	Not assessed	No evidence from a reputable source recently submitted for pathogenicity assessment of this variant. ClinVar classification is VUS with criteria provided, single submitter — insufficient to meet PS5.	clinvar
PM1	Not met	Under León-Castillo 2020 custom framework, PM1 rules apply only to specified exonuclease-domain variants (Strong: P286R, V411L, S297F, A456P, S459F; Moderate: F367S, L424I, M295R, P436R, M444K, D368Y; Supporting: A465V, L424V, T278M, A428T). p.Glu926Asp is not among these and is absent from Supplementary Table S1. Under generic ACMG, residue 926 lies within the DNA polymerase domain (aa 393-1191), not the exonuclease hotspot domain (aa 1-392) where established pathogenic missense variants cluster. No evidence of a mutational hotspot at this position.	vcep_path_250_323_s002 vcep_path_250_323
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. The allele frequency is effectively zero in control populations, meeting the PM2 threshold for rare variants in population databases (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Same-residue missense comparator search could not identify a different pathogenic amino acid change at codon 926. The pm5_candidates pipeline found no candidates, and PM5 classic same-residue semantics could not be confirmed.	pm5_candidates
PM6	Not assessed	No de novo data available. No confirmed de novo reports for NM_006231.4:c.2778G>C were identified in any reviewed source.
PP1	Not assessed	No cosegregation data available for this variant. No family studies or segregation analysis were identified.
PP2	Not assessed	HCI prior data not available for this variant. Insufficient evidence to assess whether POLE has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. POLE has both pathogenic missense variants (exonuclease domain hotspots) and likely benign missense variants across the gene.
PP3	Not met	Under León-Castillo 2020 custom framework, PP3_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and benign in silico count ≤1. p.E926D is absent from both tables. Under generic ACMG, REVEL score 0.281 is below typical pathogenic thresholds; BayesDel score -0.171963 is negative, suggesting a benign-leaning prediction; SpliceAI max delta 0.01 indicates no splicing impact. Multiple lines of computational evidence do not support a deleterious effect.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	No detailed phenotype or clinical specificity data available. The variant has been observed in clinical testing (ClinVar VUS, 1 submitter) but no specific phenotype information or syndromic features are documented.	clinvar
PP5	Not met	The sole ClinVar-attributed publication (PMID:25394175) is an ACMG/NSGC practice guideline on cancer predisposition referral indications. This paper does not mention NM_006231.4:c.2778G>C, p.Glu926Asp, or any POLE-specific variant. It does not constitute variant-specific reputable source evidence for pathogenicity.	clinvar PMID:25394175
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation in healthy adults with full penetrance expected at an early age.
BS3	Not assessed	No variant-specific functional studies demonstrating no deleterious effect for p.Glu926Asp.
BS4	Not assessed	No cosegregation data available. No family studies demonstrating lack of segregation with disease.
BP1	N/A	POLE has well-established pathogenic missense variants (e.g., exonuclease-domain hotspot mutations P286R, V411L, S297F, A456P, S459F). BP1 is intended for genes where disease is caused exclusively by truncating variants, which does not apply to POLE.	vcep_path_250_323
BP2	Not assessed	No data on observation in trans with a known pathogenic variant.
PM3	N/A	Skipped — this is a substitution variant assessed in a gene not established as recessive. PM3 applies to variants in trans with pathogenic variants in recessive disorders.
PM4	N/A	Skipped — this is a substitution variant. PM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants causing protein length change.
BP3	N/A	Skipped — this is a substitution variant. BP3 applies to in-frame deletions/insertions in repetitive regions.
BP4	Not met	Under León-Castillo 2020 custom framework, BP4_Supporting requires the variant to be present in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.E926D is absent from both tables. Under generic ACMG, REVEL 0.281 is intermediate; BayesDel -0.171963 is mildly benign-leaning but not strongly predictive across multiple tools. Multiple lines of computational evidence do not convincingly suggest no impact on the gene product.	revel bayesdel vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	No observation of an alternate molecular basis for disease in individuals carrying this variant.
BP6	Not assessed	No reputable source has classified this variant as benign. ClinVar classification is VUS with a single submitter.	clinvar
BP7	N/A	Missense variant (c.2778G>C, p.Glu926Asp). BP7 applies to synonymous/silent variants with no predicted splice impact.

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