Variant classification summary

NM_006231.4:c.2706+5G>A

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133240585 C>T · GRCh38: chr12:132663999 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

1.735091228618099e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 total allele frequency 1.74e-05, below the 0.1% rarity threshold, with no homozygotes.

2

PP3 (Supporting): SpliceAI maximum delta 0.381 (donor gain) exceeds the 0.2 threshold, predicting a splice impact.

3

Overall classification VUS: two Supporting criteria (PM2, PP3) do not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Under the usable local POLE framework's ACMG/AMP combination rules, two pathogenic Supporting criteria without PVS1, a Moderate, or a Strong criterion meet no pathogenic or benign final-category combination, resulting in 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	Not assessed	Not assessed: this intronic splice-region variant has no RNA evidence establishing a null protein consequence (p.?).	pvs1_generic_framework pvs1_variant_assessment spliceai PMID:25741868
PS1	N/A	Not applicable: as an intronic variant with no amino-acid change (p.?), no same-codon substitution can be compared.
PS2	Not assessed	Not assessed: no parental testing documents the variant as de novo in the proband.
PS3	Not assessed	Not assessed: no validated functional assay data were available; SpliceAI prediction is not a functional assay.	PMID:25741868
PS4	Not met	Not met: the POLE rule requires an exact recurrent missense hotspot, but this intronic variant is absent from COSMIC.	final_classification_framework
PM1	N/A	Not applicable: the rule applies only to missense variants in the exonuclease domain; this variant is intronic.	vcep_path_250_323
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency 1.74e-05, far below the 0.1% rarity threshold, with no homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no observations establish the variant in trans with a pathogenic variant in an affected individual.
PM4	Not assessed	Not assessed: with no established protein consequence (p.?) there is no in-frame length change to evaluate.	pvs1_variant_assessment
PM5	N/A	Not applicable: no amino-acid change (p.?) exists, so no residue with an established pathogenic missense can be compared.	PMID:25741868 pm5_candidates
PM6	Not assessed	Not assessed: no case record describes the variant as de novo without parental testing.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses were available to evaluate cosegregation.
PP2	N/A	Not applicable: PP2 applies to missense variants, and this variant is intronic with protein consequence p.?.	PMID:25741868
PP3	Met	Met (Supporting): SpliceAI maximum delta 0.381 (donor gain) exceeds the 0.2 splice-impact threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype data establish a presentation highly specific for a POLE-associated disorder.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel pathogenic assertion exists for this exact variant; only single-submitter Likely benign and VUS.	clinvar
BA1	Not met	Not met: highest gnomAD v4.1 allele frequency 3.33e-05 is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest observed allele frequency 3.33e-05 is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: zero homozygotes observed among 1,613,748 gnomAD v4.1 alleles.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated functional assay demonstrates a benign effect of this variant.	PMID:25741868
BS4	Not assessed	Not assessed: no unaffected relatives with confirmed absence of the variant were documented.
BP1	N/A	Not applicable: BP1 is a missense-specific criterion and this variant is intronic.	PMID:25741868
BP2	Not assessed	Not assessed: no phase-resolved observation places the variant in trans or in cis with a pathogenic variant.
BP3	N/A	Not applicable: this is a single-nucleotide splice-region substitution, not an in-frame indel in a repeat region.	pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI maximum delta 0.381 exceeds the 0.1 BP4 threshold, so no benign splice prediction.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis fully explaining the phenotype was identified.	clinvar
BP6	Not met	Not met: no ClinVar expert-panel benign assertion exists; a single-submitter Likely benign call is ineligible.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous coding variants, and this is an intronic splice-region change.	spliceai

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