Variant classification summary

NM_006231.4:c.62+2T>G

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133263838 A>C · GRCh38: chr12:132687252 A>C

Gene: POLE Transcript: NM_006231.4

Final call

Pathogenic

PVS1 very strong PP3 moderate PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports loss of normal POLE splicing at the canonical +2 donor site.

2

Pathogenic: PP3 moderate is met by SpliceAI maximum delta 0.989.

3

Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v4.1 (0/1,487,734 alleles).

Final determination: Under the local León-Castillo 2020 POLE framework, PVS1 at very strong plus one moderate and one supporting criterion produces a Pathogenic classification.

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	Met	Met at very strong: canonical splice-donor c.62+2T>G in the relevant POLE transcript has SpliceAI maximum delta 0.989 and no demonstrated NMD-escape downgrade.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Not applicable: the canonical splice variant has protein consequence p.?, so no amino-acid change exists for PS1 comparison.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or testing methodology are documented to establish a de novo occurrence.
PS3	Not assessed	Not assessed: SpliceAI max delta 0.989 is computational and does not substitute for a validated variant-specific functional assay with appropriate controls.	spliceai
PS4	Not met	Not met: the POLE PS4 rule requires an exact recurrent pathogenic missense variant with combined COSMIC/TCGA count >=10, but c.62+2T>G is absent and is splice-region.	vcep_path_250_323 vcep_path_250_323_s002
PM1	N/A	Not applicable: PM1 is restricted to specified exonuclease-domain missense substitutions, while this variant is intronic with protein consequence p.?.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	Met at supporting: AF 0 in gnomAD v4.1 (0/1,487,734 alleles) is below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or phased pathogenic variant in trans is documented for NM_006231.4:c.62+2T>G.
PM4	N/A	Not applicable: c.62+2T>G is a canonical intronic splice variant with p.? consequence, not an established in-frame protein-length change.	pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense residue, but this canonical splice variant has no defined protein residue or amino-acid substitution.	pm5_candidates final_classification_framework vcep_path_250_323
PM6	Not assessed	Not assessed: no published or clinical case evidence documents this variant as presumed de novo without parental testing.
PP1	Not assessed	Not assessed: no informative meioses or affected and unaffected relatives with genotype-phenotype segregation data are documented.
PP2	N/A	Not applicable: PP2 evaluates missense variation, whereas this variant is canonical splice with protein consequence p.?.	final_classification_framework vcep_path_250_323
PP3	Met	Met at moderate strength: SpliceAI maximum delta 0.989 exceeds the >=0.5 threshold for predicted splice impact.	spliceai vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical presentation is available to evaluate against a PP4 specificity rule.	vcep_path_250_323
PP5	Not assessed	Not assessed: ClinVar has no exact record or expert-panel Pathogenic/Likely pathogenic classification for c.62+2T>G.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total AF 0 (0/1,487,734 alleles), far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 total AF 0 (0/1,487,734 alleles), below the >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes and zero alleles, providing no healthy-population observation for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: SpliceAI max delta 0.989 predicts splice impact and provides no validated evidence of preserved normal function for BS3.	spliceai
BS4	Not assessed	Not assessed: no unaffected variant carriers or other informative non-segregation observations are documented.
BP1	N/A	Not applicable: BP1 addresses benign missense context, but this variant is canonical splice with protein consequence p.?.	final_classification_framework vcep_path_250_323
BP2	Not assessed	Not assessed: no cis or trans observation with a pathogenic variant is documented for NM_006231.4:c.62+2T>G.
BP3	N/A	Not applicable: the variant is a canonical splice-donor substitution, not an in-frame indel in a repetitive protein region.	pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI maximum delta 0.989 exceeds the <=0.1 threshold for BP4 supporting evidence.	spliceai vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no phenotype, alternative molecular diagnosis, or competing cause is available to evaluate BP5.	vcep_path_250_323
BP6	Not assessed	Not assessed: ClinVar has no exact record or expert-panel Benign/Likely benign classification for c.62+2T>G.	clinvar
BP7	N/A	Not applicable: c.62+2T>G is an intronic canonical splice variant, not a synonymous coding variant eligible for BP7.

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.