Variant classification summary

NM_006231.4:c.1924-5C>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133245328 G>A · GRCh38: chr12:132668742 G>A

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

4.337470040474792e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is extremely rare in gnomAD, with non-cancer AF 6.75776e-06.

2

BP4 supporting: SpliceAI maximum delta 0.084 is below the <=0.1 benign threshold.

Final determination: The local POLE framework retains ACMG/AMP combination logic; conflicting PM2 Supporting and BP4 Supporting evidence without a qualifying pathogenic or benign combination yields 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: c.1924-5C>T is a splice-region SNV at -5, outside the canonical ±1,2 PVS1 null-variant positions, with no demonstrated abnormal transcript or NMD.	pvs1_variant_assessment pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: c.1924-5C>T is splice-region intronic with p.? rather than a missense amino-acid change.
PS2	Not assessed	Not assessed: no proband-parent genotypes, confirmed parentage, or documented absence of the variant in both parents are available.
PS3	Not assessed	Not assessed: no controlled RNA, minigene, protein, or other validated functional assay is reported for c.1924-5C>T; SpliceAI 0.084 is computational, not PS3 evidence.
PS4	Not met	Not met: the exact splice-region variant is absent from the governing recurrence tables and is not one of the specified pathogenic POLE missense hotspots.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM1	N/A	Not applicable: POLE PM1 is missense-specific, while c.1924-5C>T is intronic with p.? and no mapped protein residue.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at supporting strength: gnomAD v3.1 non-cancer AF is 6.75776e-06, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic second allele, or phase evidence establishes this variant in trans for PM3.
PM4	N/A	Not applicable: the intronic SNV has protein consequence p.? and provides no demonstrated protein-length change required for PM4.	pvs1_variant_assessment
PM5	N/A	Not applicable: p.? supplies no amino-acid residue, so alternate pathogenic missense changes cannot be compared at the same position.	pm5_candidates
PM6	Not assessed	Not assessed: no clinical report describes this variant as de novo with unconfirmed parentage or provides supporting proband and parental data.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family segregation results are reported for this variant.
PP2	N/A	Not applicable: PP2 concerns missense variation, whereas c.1924-5C>T is an intronic splice-region variant with p.?.
PP3	Not met	Not met: SpliceAI maximum delta 0.084 is below the >=0.2 PP3 supporting threshold.	spliceai
PP4	Not assessed	Not assessed: no patient-level, highly specific POLE-related phenotype is available for comparison with the PP4 requirement.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the highest reported allele frequency is 0.000201694, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest reported allele frequency is 0.000201694, below the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but no documented unaffected carrier or healthy-adult observation is available for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no controlled assay demonstrates normal splicing or protein function for c.1924-5C>T, and SpliceAI 0.084 cannot establish BS3.
BS4	Not assessed	Not assessed: no affected, well-phenotyped individual lacking the variant or documented non-segregation analysis is available.
BP1	N/A	Not applicable: BP1 is a missense criterion, but c.1924-5C>T is intronic splice-region with p.?.
BP2	Not assessed	Not assessed: no documented co-occurring pathogenic variant or cis/trans phase result supports BP2 for this variant.
BP3	N/A	Not applicable: c.1924-5C>T is a splice-region SNV, not a neutral in-frame coding indel in a repetitive protein region.	pvs1_variant_assessment
BP4	Met	Met, supporting: SpliceAI maximum delta 0.084 meets the <=0.1 BP4 supporting threshold.	spliceai
BP5	Not assessed	Not assessed: no governing BP5 specification or validated BP5-specific evidence is available for this variant.	vcep_path_250_323 clinvar
BP6	Not met	Not met: ordinary Likely benign laboratory submissions cannot trigger BP6 because ClinVar reports zero expert-panel submissions.	clinvar
BP7	N/A	Not applicable: the variant is splice-region intronic, not synonymous, so BP7 is out of 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.