Variant classification summary

NM_006231.4:c.4291-30_4291-27delinsAAT

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133220173 CAAG>ATT · GRCh38: chr12:132643587 CAAG>ATT

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (supporting): the variant is absent from gnomAD v2.1 and v4.1 at an allele frequency of 0, supporting rarity only at supporting strength.

Final determination: Under the Leon-Castillo 2020 POLE framework's retained generic ACMG/AMP 2015 combination rules, one supporting pathogenic criterion (PM2) reaches no Pathogenic or Likely Pathogenic combination and therefore defaults to Variant of Uncertain Significance.

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	Not applicable: the variant is fully intronic with no predicted protein change (NP_006222.2:p.?) and SpliceAI max delta 0.135, below the 0.2 support threshold.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai final_classification_framework
PS1	N/A	Not applicable: an intronic p.? delins (no amino-acid change) has no residue to match an established pathogenic missense.	clinvar final_classification_framework
PS2	Not assessed	Not assessed: no parental testing or proband phenotype data available to confirm a de novo occurrence.	final_classification_framework vcep_path_250_323
PS3	Not assessed	Not assessed: no functional assay data (minigene or RNA study) exists for this intronic POLE variant, so a damaging-effect claim cannot be made.	spliceai
PS4	Not met	Not met: variant is intronic (p.?) and absent from Supplementary Table S1, so combined endometrial-carcinoma count 0 >= 10 fails.	vcep_path_250_323_s002 vcep_path_250_323
PM1	N/A	Not applicable: an intronic p.? variant lies in no protein hotspot/domain, and is absent from the framework's exonuclease-domain missense lists.	vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PM2	Met	Met at supporting: absent from gnomAD v2.1 and v4.1 (allele frequency 0), below the <=0.0001 PM2 supporting threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no proband genotype, phase, or second POLE variant is available, so the trans configuration PM3 requires cannot be established.	final_classification_framework vcep_path_250_323 clinvar
PM4	N/A	Not applicable: the intronic c.4291-30_4291-27delinsAAT leaves the POLE protein unchanged (NP_006222.2:p.?), so no in-frame coding indel or protein length change is present.	pvs1_variant_assessment final_classification_framework vcep_path_250_323
PM5	N/A	Not applicable: an intronic p.? delins has no residue, so no same-residue pathogenic comparator can apply.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no proband phenotype or family data available to support an assumed de novo occurrence.	final_classification_framework vcep_path_250_323
PP1	Not assessed	Not assessed: no family pedigree or genotype data available to evaluate co-segregation with disease.	final_classification_framework vcep_path_250_323
PP2	N/A	Not applicable: PP2 is restricted to missense variants, and this intronic p.? delins is not a missense change.	final_classification_framework
PP3	Not met	Not met: SpliceAI max delta 0.135 is below the 0.2 PP3 supporting threshold for this intronic variant.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323
PP4	Not assessed	Not assessed: no clinical phenotype or HPO terms were supplied for this case, so phenotype specificity cannot be evaluated.
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel Pathogenic/Likely-pathogenic classification exists to trigger PP5.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1 and v4.1 (allele frequency 0), far below the >=0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: absent from gnomAD v2.1 and v4.1 (allele frequency 0) versus the >=0.01 BS1 strong-benign threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: zero carrier or homozygous observations exist because the variant is absent from gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data (minigene or RNA study) exists for this intronic POLE variant, so a no-damaging-effect claim cannot be made.	spliceai
BS4	Not assessed	Not assessed: no family genotype data available to evaluate non-segregation of the variant with disease.	final_classification_framework vcep_path_250_323
BP1	N/A	Not applicable: BP1 is restricted to missense variants, and this intronic p.? delins is not a missense change.	final_classification_framework
BP2	Not assessed	Not assessed: no co-occurring pathogenic variant or phase data exists, so the cis/trans observation BP2 requires cannot be made.	final_classification_framework vcep_path_250_323 clinvar
BP3	N/A	Not applicable: c.4291-30_4291-27delinsAAT is fully intronic with an unchanged protein product, not an in-frame coding indel within a repetitive region.	pvs1_variant_assessment final_classification_framework
BP4	Not met	Not met: SpliceAI max delta 0.135 exceeds the <=0.1 BP4 supporting threshold for this intronic variant.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323
BP5	Not assessed	Not assessed: no case-level information on a second pathogenic variant or alternative molecular cause was available to test BP5.
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel Benign/Likely-benign classification exists to trigger BP6.	clinvar
BP7	N/A	Not applicable: an intronic c.4291-30_4291-27delinsAAT is not a synonymous coding variant, so BP7 is out of scope.

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