NM_006231.3:c.4189C>A

POLE · NP_006222.2:p.(Leu1397Ile) · NM_006231.3

GRCh37: chr12:133220524 G>T · GRCh38: chr12:132643938 G>T

Gene: POLE Transcript: NM_006231.3

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.3

Protein

NP_006222.2:p.(Leu1397Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength.

No other pathogenic or benign criteria are met. The variant is a C-terminal missense change outside the exonuclease domain, with no functional data, no clinical observations, no segregation data, and indeterminate computational predictions (REVEL 0.329, BayesDel -0.262).

With only PM2_Supporting met, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient to classify as benign or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Final determination: Per ACMG/AMP 2015 (PMID:25741868), criteria combinations that do not meet any pathogenic, likely pathogenic, benign, or likely benign threshold default to Variant of Uncertain Significance (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	This is a missense variant (p.Leu1397Ile), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework per PMC6185798 does not apply to missense substitutions.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No pathogenic missense variant has been identified at codon 1397. The variant is absent from ClinVar, and no same-residue pathogenic comparator exists in the literature or curated databases.	clinvar pm5_candidates
PS2	Not met	No de novo observations have been reported for NM_006231.3:c.4189C>A. No family or parent-of-origin data are available.
PS3	Not met	No functional studies have been performed on p.Leu1397Ile or a systematically characterized range that includes residue 1397. OncoKB reports Unknown Oncogenic Effect. Position 1397 is far C-terminal, well outside the exonuclease domain (residues ~268–471), and not covered by any known tiling/saturation mutagenesis dataset.	oncokb
PS4	Not met	The variant is absent from the León-Castillo Supplementary Table S1 and is not recurrent in COSMIC or TCGA endometrial carcinoma cohorts. Custom PS4_Supporting requires recurrence in both cohorts with combined EC count ≥10 and membership in the established pathogenic set, which are not met. No germline case-control enrichment data exist.	vcep_path_250_323_s002 clinvar
PS5	N/A	This variant is absent from ClinVar and has no prior ClinGen-approved pathogenic classification to evaluate.	clinvar
PM1	Not met	Residue 1397 is in the C-terminal region of POLE, well outside the exonuclease domain (residues ~268–471). The León-Castillo custom PM1 framework applies only to five established exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F) and specific recurrent pathogenic or uncertain-tier variants, none of which include p.Leu1397Ile. Position 1397 is not in a known functional domain or mutational hotspot.	vcep_path_250_323_s002
PM2	Met	NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not observed in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants were identified. Automated PM5 candidate harvesting was unable to confirm classic same-residue semantics for p.Leu1397Ile.	pm5_candidates
PM6	Not met	No de novo observations of NM_006231.3:c.4189C>A have been reported. No parent-of-origin or confirmed maternity/paternity data are available.
PP1	Not met	No segregation data are available for NM_006231.3:c.4189C>A. The variant has not been observed in families with disease, and no co-segregation analysis has been performed.
PP2	Not met	No HCI prior score is available for this variant. While POLE has disease-associated missense variants in the exonuclease domain, residue 1397 is in a C-terminal region with unknown functional significance, and REVEL score (0.329) is indeterminate. Insufficient evidence to apply PP2.	revel bayesdel
PP3	Not met	The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (below pathogenic threshold of ~0.5), BayesDel score -0.262205 leans benign, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple computational lines do not support a deleterious effect.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not met	No clinical phenotype data are available for NM_006231.3:c.4189C>A. The variant has not been reported in affected individuals, and no phenotype specificity analysis can be performed.
PP5	Not met	No reputable source has classified NM_006231.3:c.4189C>A as pathogenic. The variant is absent from ClinVar and has not been evaluated by any expert panel.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency of 0 does not meet the >1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from all population databases. Allele frequency of 0 does not meet the >0.3% threshold for BS1; BS1 requires the variant to be observed at a frequency too high for a disease-causing variant.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous or compound heterozygous observations of NM_006231.3:c.4189C>A have been reported. The variant is absent from gnomAD, so no homozygote count data exist.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies have been performed demonstrating a benign effect for p.Leu1397Ile. No variant-specific or range-based experimental data are available to assess functional impact.	oncokb
BS4	Not met	No segregation or family data are available for NM_006231.3:c.4189C>A. Lack of cosegregation with disease in affected families cannot be assessed.
BP1	Not met	Although this is a missense variant, POLE disease mechanism is not restricted to loss-of-function/truncating variants. Pathogenic missense variants in the exonuclease domain (e.g., P286R, V411L) are well-established in somatic disease. BP1 is not applicable when the gene's disease mechanism includes missense changes.	vcep_path_250_323
BP2	Not met	No co-occurrence data are available. The variant has not been observed in trans with a known pathogenic POLE variant, nor has it been observed in cis with a pathogenic variant in any reported case.
BP4	Not met	The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom BP4_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (neither clearly benign nor clearly pathogenic), BayesDel -0.262205 is mildly benign-leaning, and SpliceAI predicts no splicing impact. The computational evidence is equivocal and does not meet the threshold for BP4, which requires multiple lines of computational evidence suggesting no impact.	revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not met	No reputable source has classified NM_006231.3:c.4189C>A as benign. The variant is absent from ClinVar and has not been reported in any curated clinical database.	clinvar
BP6	Not met	No reputable source has classified NM_006231.3:c.4189C>A as benign. The variant is absent from ClinVar and has no expert panel benign classification.	clinvar
BP7	N/A	This is a missense variant (c.4189C>A, p.Leu1397Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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