LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-30
Case ID: NM_006231.3_c.1763T_C_20260730_172735
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

POLE  · NP_006222.2:p.(Val588Ala)  · NM_006231.3
GRCh37: chr12:133248832 A>G  ·  GRCh38: chr12:132672246 A>G
Gene: POLE Transcript: NM_006231.3
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.3
Protein
NP_006222.2:p.(Val588Ala)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_006231.3:c.1763T>C (p.Val588Ala) is a missense variant in POLE, the catalytic subunit of DNA polymerase epsilon. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
2
Multiple computational predictors suggest a benign effect: REVEL score 0.26, BayesDel score -0.437986, and SpliceAI delta score 0.00 (BP4_Supporting).
3
Residue 588 lies outside the POLE exonuclease domain (residues ~268–471) and is not one of the established pathogenic hotspot residues identified by León-Castillo et al. 2020. The variant is absent from COSMIC and has not been reported as a recurrent somatic mutation in endometrial carcinoma.
4
No variant-specific functional data, de novo observations, co-segregation data, or ClinVar classifications were identified for this variant. OncoKB reports an unknown oncogenic effect with no variant-level curated evidence.
5
The overall evidence profile yields PM2_Supporting (1 pathogenic supporting criterion) and BP4_Supporting (1 benign supporting criterion). These offset to a variant of uncertain significance (VUS) per ACMG/AMP 2015 classification 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 PVS1 is not applicable: NM_006231.3:c.1763T>C is a missense substitution (p.Val588Ala) and does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).
pvs1_generic_framework
PS1 N/A No known pathogenic variant with the same amino acid change (p.Val588Ala) has been identified. This variant is absent from ClinVar entirely; no prerequisite pathogenic comparator exists for PS1.
clinvar
PS2 N/A No de novo confirmation data available for this variant. No publications identified in the literature search.
PS3 Not met No variant-specific functional data identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. V588A is absent from the León-Castillo et al. 2020 supplementary tables (S1–S3) and was not identified in any published functional study. No systematic range characterization encompassing residue 588 was found.
oncokb vcep_path_250_323
PS4 Not met Under the Leon-Castillo custom framework, PS4_Supporting requires the exact variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count ≥10, which V588A does not satisfy (absent from COSMIC and supplementary tables). Under generic ACMG, no case-control or observational data exist to support increased prevalence in affected individuals.
vcep_path_250_323_s002
PS5 N/A No established pathogenic missense variant has been identified at the same amino acid residue (Val588). ClinVar contains no entries for any POLE variant at this position, and PM5 candidate harvesting found no same-residue pathogenic comparators.
clinvar
PM1 Not met Residue 588 lies outside the POLE exonuclease domain (residues ~268–471). V588A is not one of the established hotspot mutations in the León-Castillo custom framework (P286R, V411L, S297F, A456P, S459F for Strong; F367S, L424I, M295R, P436R, M444K, D368Y for Moderate; A465V, L424V, T278M, A428T for Supporting). The variant is not located in a statistically significant cancer hotspot per cancerhotspots.org. No critical functional domain characterized in the literature encompasses this residue.
vcep_path_250_323 vcep_path_250_323_s002
PM2 Met This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP, absence from large population databases supports pathogenicity at supporting strength for a gene where pathogenic missense variants are an established disease mechanism.
gnomad_v2 gnomad_v4 gnomad_canada
PM5 N/A No same-residue pathogenic comparator variants identified. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics; no ClinVar pathogenic variants at residue 588 were found.
PM6 N/A No de novo data available for this variant. PM6 requires a confirmed de novo observation, and no such data were identified.
PP1 N/A No co-segregation data available for this variant.
PP2 Not assessed While POLE has established pathogenic missense variants (exonuclease domain hotspots) supporting that missense changes are a disease mechanism, the HCI prior constraint data is unavailable for this transcript, precluding reliable assessment of the gene's rate of benign missense variation. PP2 cannot be applied without constraint metrics.
PP3 Not met V588A is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic ACMG, REVEL score 0.26 (below pathogenic threshold of 0.5) and BayesDel score -0.437986 (benign range) do not support a damaging prediction. Multiple in silico tools predict a tolerated or benign effect.
revel bayesdel vcep_path_250_323_s003 vcep_path_250_323_s004
PP4 N/A No patient phenotype or clinical data available for specificity assessment.
PP5 N/A Variant is absent from ClinVar. No reputable source classification exists to support PP5.
clinvar
BA1 Not met Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0%). This is well below the BA1 threshold of >1%.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met Variant is absent from gnomAD (allele frequency 0%). This is below the BS1 threshold of >0.3% for a gene where pathogenic missense variants are observed.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 N/A Variant has not been observed in any population database; cannot assess whether it has been seen in healthy adult individuals. BS2 requires observation in a healthy individual for a disorder with full penetrance expected at an early age.
BS3 Not met No functional studies demonstrating a neutral or benign effect for this variant. No variant-specific functional data identified in the literature, OncoKB, or the León-Castillo supplementary materials.
oncokb vcep_path_250_323
BS4 N/A No family segregation data available to assess non-segregation with disease.
BP1 N/A BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. POLE has well-established pathogenic missense variants (including the five exonuclease-domain hotspot mutations P286R, V411L, S297F, A456P, S459F), so the BP1 premise does not hold.
vcep_path_250_323
BP2 N/A No data on observation in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4 Met Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.26 (below 0.5 pathogenic threshold, consistent with benign), BayesDel score -0.437986 (negative, indicating tolerated/benign), and SpliceAI max delta score 0.00 (predicting no splice alteration). Three independent computational predictors converge on a benign interpretation, meeting the BP4 threshold.
revel bayesdel spliceai
BP5 N/A Variant is absent from ClinVar. No alternative molecular basis has been identified to explain the phenotype.
clinvar
BP6 N/A Variant is absent from ClinVar. No reputable source has classified this variant as benign.
clinvar
BP7 N/A BP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_006231.3:c.1763T>C is a missense variant (p.Val588Ala), not a synonymous change.
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