Variant classification summary

NM_006231.4:c.5174-15C>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133218452 G>A · GRCh38: chr12:132641866 G>A

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

5.010038865376498e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting reflects the variant's extremely low gnomAD v4.1 frequency and zero observed homozygotes.

Final determination: Under the custom POLE framework's ACMG/AMP combination rules, one Supporting pathogenic criterion alone satisfies neither a pathogenic nor a benign rule, so the result is 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	N/A	Not applicable: the intronic SNV is at c.-15, outside the named PVS1 null-variant classes and canonical +1/+2 splice sites, with SpliceAI maximum delta 0.068.	pvs1_variant_assessment spliceai
PS1	N/A	Not applicable: the intronic variant has protein consequence p.?, so no same-amino-acid pathogenic change can be evaluated.
PS2	Not assessed	Not assessed: no documented proband de novo result with confirmation of both maternity and paternity is available.
PS3	Not assessed	Not assessed: No variant-specific functional assay with validated controls or a reproducible damaging result is documented.
PS4	N/A	Not applicable: the POLE PS4 rule requires an exact recurrent missense hotspot, whereas c.5174-15C>T is intronic with protein consequence p.?.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM1	N/A	Not applicable: the POLE framework limits PM1 to exact exonuclease-domain missense substitutions, while this variant is intronic with protein consequence p.?.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at Supporting: gnomAD v4.1 AF 5.01004e-06 is below the <=0.0001 PM2 threshold, with zero homozygotes among 1,596,794 alleles.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no recessive inheritance context, pathogenic second allele, or parent/offspring testing establishes this variant in trans.
PM4	N/A	Not applicable: c.5174-15C>T is an intronic SNV with protein consequence p.?, not an in-frame indel or stop-loss variant causing a protein-length change.	pvs1_variant_assessment
PM5	N/A	Not applicable: protein consequence p.? provides no amino-acid residue for comparison with a different pathogenic missense change.
PM6	Not assessed	Not assessed: no affected proband with an assumed de novo variant and unconfirmed parental origin is documented.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to evaluate co-segregation.
PP2	N/A	Not applicable: PP2 is a missense criterion, but this variant is intronic with protein consequence p.?.
PP3	N/A	Not applicable: the POLE PP3 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.	vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no patient phenotype or family-history evidence is available to compare with a single-etiology disease presentation.
PP5	Not met	Not met: ClinVar reports one non-expert single-laboratory Likely benign submission, not an exact-variant Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 7.9e-07 is far below the >=0.05 BA1 threshold, despite a Finnish point estimate of 4.0422e-05.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF 7.9e-07 is below the generic >=0.01 BS1 threshold and does not exceed the disorder-expected frequency.	gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes among 1,596,794 alleles, with no documented qualifying healthy-adult observation.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: No variant-specific functional assay with validated controls or a reproducible nondamaging result is documented.
BS4	Not assessed	Not assessed: no affected relatives with known variant status are documented to demonstrate lack of segregation.
BP1	N/A	Not applicable: BP1 is a missense criterion, but this variant is intronic with protein consequence p.?.
BP2	Not assessed	Not assessed: no family or proband data establish the variant in trans with a pathogenic dominant allele or in cis with any pathogenic variant.
BP3	N/A	Not applicable: the variant is a single intronic SNV, not the in-frame deletion or insertion required for BP3, so repeat-region context cannot trigger it.	pvs1_variant_assessment
BP4	N/A	Not applicable: the POLE BP4 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.	vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no evidence documents an alternate molecular basis for disease in the case carrying this variant.
BP6	Not met	Not met: the exact variant has only a non-expert single-laboratory Likely benign ClinVar submission, not a qualifying reputable-source benign report under the required rule.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, but c.5174-15C>T is intronic with p.?, so its SpliceAI max delta 0.068 is outside BP7 scope.

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.