Variant classification summary

NM_006231.4:c.1794+19G>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133248782 C>A · GRCh38: chr12:132672196 C>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

1.2753166292361235e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): essentially absent from population databases - only 2/1,568,238 alleles in gnomAD v4.1 and none in gnomAD v2.1 or gnomAD-Canada v1.0, below the 0.1% rare-variant threshold.

2

BP4 (Supporting): SpliceAI max delta 0.031 is below the <0.1 threshold, predicting no significant splice impact.

3

Synthesis: with only PM2_Supporting and BP4_Supporting, no pathogenic or benign ACMG/AMP 2015 combination is reached, yielding a classification of VUS.

Final determination: Under the local POLE framework's ACMG/AMP final-combination rules, one supporting pathogenic criterion and one supporting benign criterion is an unclassified combination and therefore 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: deep intronic substitution with no defined protein consequence (p.?) and SpliceAI max delta 0.031, predicting no loss-of-function splice alteration.	pvs1_generic_framework pvs1_variant_assessment spliceai
PS1	N/A	Not applicable: no amino-acid substitution is established for this intronic variant (p.?), so the same-amino-acid criterion cannot apply.
PS2	Not assessed	Not assessed: no parental testing results establish that the variant is absent from both biological parents (de novo).
PS3	Not assessed	Not assessed: no validated functional assay evidence for this variant was available to demonstrate a damaging effect.
PS4	Not assessed	Not assessed: the POLE framework's PS4 applies only to recurrent missense hotspots, and no case-control enrichment data exist for this intronic variant.	final_classification_framework
PM1	N/A	Not applicable: the intronic variant affects no protein residue, so exonuclease-domain hotspot evidence cannot be assigned.
PM2	Met	Met (Supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with only 2/1,568,238 alleles (AF 1.28e-06) in gnomAD v4.1, below the 0.1% rare-variant threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations, pathogenic allele in the same gene, or phase data establish a trans configuration.
PM4	N/A	Not applicable: an intronic substitution with no protein-length change, so the in-frame indel/stop-loss criterion does not apply.	pvs1_variant_assessment
PM5	N/A	Not applicable: no protein residue or missense change is established, so comparison with a pathogenic variant at the same residue is impossible.
PM6	Not assessed	Not assessed: no parental testing or phenotype concordance data support a de novo occurrence.
PP1	Not assessed	Not assessed: no pedigree or segregation data from affected or unaffected relatives were available.
PP2	N/A	Not applicable: the variant has no missense consequence, so the gene-level missense mechanism criterion cannot be assigned.
PP3	Not met	Not met: SpliceAI max delta 0.031 is below the >0.2 PP3 threshold, predicting no splice impact.	spliceai generic_acmg_combination_rules final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no individual or tumor phenotype data establish a presentation highly specific to POLE-related disease.
PP5	Not met	Not met: the ClinVar record has no expert-panel submission, only a single clinical laboratory assertion.	clinvar
BA1	Not met	Not met: the highest allele frequency (3.28e-05) is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: the highest allele frequency (3.28e-05) is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no evidence documents carriers as phenotypically healthy adults, so benign homozygosity cannot be established.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence demonstrated a benign effect; the single-submitter Likely benign ClinVar entry is not functional evidence.
BS4	Not assessed	Not assessed: no unaffected-carrier relatives or non-segregating meioses were documented.
BP1	N/A	Not applicable: the variant has no missense consequence, so the truncating-disease missense rule does not apply.
BP2	Not assessed	Not assessed: no co-occurrence of the variant with a pathogenic allele or cis/trans phase data were available.
BP3	N/A	Not applicable: the variant is not an in-frame insertion/deletion, so there is no repeat-region change to evaluate.	pvs1_variant_assessment
BP4	Met	Met (Supporting): SpliceAI max delta 0.031 is below the <0.1 BP4 threshold, predicting no significant splice impact.	spliceai generic_acmg_combination_rules final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no carrier genotype or phenotype data show the phenotype is explained by an alternative molecular diagnosis.
BP6	Not met	Not met: the single Likely benign laboratory submission cannot trigger BP6 because the record has no expert-panel submission.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous coding substitutions, and this variant is intronic.

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.