Variant classification summary

NM_006231.4:c.331-30G>A

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133256662 C>T · GRCh38: chr12:132680076 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

3.373347059940629e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely low population frequency — gnomAD v4.1 AF 0.0034% with zero homozygotes in ~1.6 million alleles (flagged for human review: not literally absent, 54 carriers).

2

BP4 (Supporting): SpliceAI max delta 0.06, below the <0.1 threshold, predicting no effect on splicing.

3

Overall classification: VUS — one supporting pathogenic (PM2) plus one supporting benign (BP4) criterion matches no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Under the governing local custom POLE framework (Leon-Castillo et al. 2020 v1), which retains standard ACMG/AMP 2015 final-combination thresholds (identical to generic_acmg_combination_rules, PMID:25741868): with only one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) applied, no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule is satisfied; conflicting single-supporting evidence on both sides yields 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	Not met	Not met: intronic variant with no null-variant mechanism and SpliceAI max delta 0.06, below any splice-disruption evidence threshold.	spliceai pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:25741868 final_classification_framework
PS1	N/A	Not applicable: intronic variant with no amino acid change (p.?), so no protein consequence exists to compare with established pathogenic variants.	PMID:25741868
PS2	Not assessed	Not assessed: no de novo observation, parental testing, or identity confirmation data exist for this variant.
PS3	Not assessed	Not assessed: no variant-specific functional studies (RNA, minigene, or enzyme-activity assays) were available.	PMID:25741868 clinvar
PS4	Not assessed	Not assessed: insufficient case-level evidence was available to evaluate this criterion.
PM1	N/A	Not applicable: the POLE framework restricts PM1 to exonuclease-domain missense hotspots; this intronic variant (p.?) is outside that scope.	vcep_path_250_323 vcep_path_250_323_s002 PMID:25741868
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 0.0034% with zero homozygotes in ~1.6 million alleles, an extremely low frequency. Flagged for human review: the variant is not literally absent from gnomAD (54 carriers), so this relies on the extremely-low-frequency reading.	PMID:25741868 gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no proband or family genotype data exist to determine trans configuration with a pathogenic POLE variant.	PMID:25741868 clinvar gnomad_v4
PM4	N/A	Not applicable: intronic substitution with no protein-length-change mechanism (not an in-frame indel or stop-loss variant).	PMID:25741868 final_classification_framework
PM5	N/A	Not applicable: intronic variant with no amino acid change, so no comparison with known pathogenic missense at the same residue is possible.	pm5_candidates PMID:25741868
PM6	Not assessed	Not assessed: no parental samples or family-history evidence of de novo occurrence was available.
PP1	Not assessed	Not assessed: no affected family members have been genotyped, so no segregation data exist for this variant.
PP2	N/A	Not applicable: PP2 applies only to missense variants; this is an intronic variant (p.?).	PMID:25741868
PP3	Not met	Not met: SpliceAI max delta 0.06 is below the >0.2 PP3 threshold, predicting no splice impact.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules
PP4	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PP5	Not assessed	Not assessed: the only ClinVar record is a 1-star single-submitter VUS, not a reputable-source pathogenic rating.
BA1	Not met	Not met: highest observed allele frequency 0.0046% (gnomAD v4.1 non-Finnish European) is ~1000-fold below the 5% BA1 threshold.	PMID:25741868 gnomad_v2 gnomad_v4
BS1	Not met	Not met: observed allele frequency (max 0.0046%) is orders of magnitude below any frequency expected for these rare POLE disorders.	PMID:25741868 gnomad_v2 gnomad_v4
BS2	Not met	Not met: zero homozygotes in ~1.85 million alleles, and the adult-onset POLE phenotype does not meet the early full-penetrance requirement.	PMID:25741868 gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no mRNA-level functional studies (patient RNA or minigene splicing assays) were available for this variant.	PMID:25741868 spliceai clinvar
BS4	Not assessed	Not assessed: no family studies exist to document lack of segregation in affected members.
BP1	Not met	Not met: variant is intronic, and POLE's established disease mechanism is missense, not primarily truncating.	vcep_path_250_323 PMID:25741868
BP2	Not assessed	Not assessed: no cis/trans phase determination with a pathogenic POLE variant was available.	PMID:25741868 clinvar gnomad_v4
BP3	N/A	Not applicable: single-nucleotide intronic substitution, not an in-frame indel in a repeat region.	PMID:25741868 final_classification_framework
BP4	Met	Met (supporting): SpliceAI max delta 0.06 is below the <0.1 BP4 threshold, predicting no impact on splicing.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules PMID:25741868
BP5	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP6	Not assessed	Not assessed: the only ClinVar record is a 1-star single-submitter VUS, providing no reputable-source benign rating.
BP7	N/A	Not applicable: BP7 applies to synonymous coding variants; this is an intronic variant.	PMID:25741868 spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.