Variant classification summary

NM_006231.4:c.6658-19C>G

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133201599 G>C · GRCh38: chr12:132625013 G>C

Gene: POLE Transcript: NM_006231.4

Final call

VUS

BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

7.426397535684152e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI max delta 0.075 falls below the <0.1 threshold, indicating no predicted splice impact.

2

Overall: VUS - with BP4 the only criterion met, no benign or pathogenic combination rule is satisfied, so the residual 'all other combinations' rule applies.

Final determination: Under the governing local custom POLE gene framework (Leon-Castillo et al. 2020 package; no ClinGen CSPEC exists for POLE), which retains the ACMG/AMP 2015 final-category thresholds, the sole met criterion is BP4 (supporting), and with no BA1, no strong benign criterion, and no second supporting benign criterion the evidence matches no Benign, Likely Benign, Likely Pathogenic, or Pathogenic rule, so it falls to the residual 'all other combinations' category: 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 met	Not met: the variant is not a nonsense, frameshift, or canonical splice-site change, and SpliceAI max delta 0.075 predicts no splicing effect.	spliceai pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: the intronic variant produces no amino acid change (p.?) to compare against an established pathogenic variant.	PMID:25741868
PS2	Not assessed	Not assessed: no proband description, parental genotypes, or de novo observations were available.	clinvar PMID:25741868
PS3	Not assessed	Not assessed: no functional study of this exact variant - RNA analysis, minigene assay, or other - was available.	PMID:25741868 spliceai clinvar vcep_path_250_323
PS4	Not assessed	Not assessed: insufficient evidence was available.
PM1	N/A	Not applicable: no amino acid residue is altered (p.?), so none can fall within a hotspot or critical domain.	vcep_path_250_323
PM2	Not assessed	Not assessed: insufficient evidence was available.
PM3	Not assessed	Not assessed: no affected-proband or allele-phase data was available, and this POLE disorder is autosomal dominant rather than recessive.	PMID:25741868 clinvar gnomad_v4 gnomad_v2
PM4	N/A	Not applicable: a single-nucleotide intronic substitution, not an in-frame indel or stop-loss change, so no protein length change is produced.	PMID:25741868
PM5	N/A	Not applicable: no missense change occurs (p.?), so there is no residue to compare with an established pathogenic substitution.	PMID:25741868
PM6	Not assessed	Not assessed: no proband genotype, family testing, or assumed-de-novo observation was available.	clinvar PMID:25741868
PP1	Not assessed	Not assessed: no segregation data - affected-family genotypes or informative meioses - was available.	clinvar PMID:25741868
PP2	N/A	Not applicable: the variant is intronic with no amino acid change, so it is not a missense variant.	PMID:25741868
PP3	Not met	Not met: SpliceAI max delta 0.075 is below the >0.2 supporting threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: insufficient evidence was available.
PP5	Not assessed	Not assessed: insufficient evidence was available.
BA1	Not assessed	Not assessed: insufficient evidence was available.
BS1	Not assessed	Not assessed: insufficient evidence was available.
BS2	Not assessed	Not assessed: insufficient evidence was available.
BS3	Not assessed	Not assessed: no well-established functional study of this exact variant was available to show an absence of damaging effect.	PMID:25741868 spliceai clinvar vcep_path_250_323
BS4	Not assessed	Not assessed: no affected-family genotypes or non-segregation observations were available.	clinvar PMID:25741868
BP1	N/A	Not applicable: not a missense variant (p.?), and POLE disease is driven by missense rather than truncating variants.	PMID:25741868
BP2	Not assessed	Not assessed: no co-occurrence or allele-phase observation with a pathogenic POLE allele was available.	PMID:25741868 clinvar gnomad_v4 gnomad_v2
BP3	N/A	Not applicable: the variant is a single-nucleotide substitution, not an in-frame indel in a repeat region.	PMID:25741868 gnomad_canada
BP4	Met	Met (supporting): SpliceAI max delta 0.075 is below the <0.1 threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: insufficient evidence was available.
BP6	Not assessed	Not assessed: insufficient evidence was available.
BP7	N/A	Not applicable: the variant is deep intronic rather than a synonymous coding change; the no-splice-impact evidence is captured under BP4.

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