NM_006231.4:c.286-8C>G

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133256816 G>C · GRCh38: chr12:132680230 G>C

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

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v2.1 and v4.1 (AF=0), consistent with a rare disease-associated allele.

BP4 (Supporting): SpliceAI max delta 0.08, below the 0.1 threshold, predicts no significant splice impact.

Final classification: VUS — one pathogenic-supporting and one benign-supporting criterion satisfy no qualifying ACMG combination rule.

Final determination: Under the León-Castillo 2020 custom POLE framework, which retains the standard ACMG/AMP 2015 final combination thresholds, the only met criteria are PM2 (supporting, pathogenic direction) and BP4 (supporting, benign direction); this 1-supporting-pathogenic + 1-supporting-benign combination is conflicting evidence satisfying no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule, so the final call is 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: no null-allele effect predicted — SpliceAI max delta 0.08, below the 0.1 threshold.	pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context spliceai generic_acmg_combination_rules final_classification_framework
PS1	N/A	Not applicable: an intronic variant with no amino acid change (p.?), so no same-residue pathogenic comparison can exist.	generic_acmg_combination_rules PMID:28492532
PS2	Not assessed	Not assessed: no proband-parent trio data with confirmed parentage was available to evaluate a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay evidence, such as RNA or minigene studies, was available for this variant.	generic_acmg_combination_rules spliceai PMID:28492532 clinvar vcep_path_250_323 gnomad_v2 gnomad_v4
PS4	Not assessed	Not assessed: no case-control, cohort, or somatic-recurrence data existed for this variant in any source.	vcep_path_250_323 vcep_path_250_323_s002 clinvar PMID:28492532
PM1	N/A	Not applicable: the POLE framework restricts PM1 to exact exonuclease-domain missense hotspots; this variant is intronic.	vcep_path_250_323 vcep_path_250_323_s002 generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1 and v4.1 (AF=0), below the <0.1% ultra-rare threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no second POLE variant or phase data was available to establish a trans configuration.	clinvar PMID:28492532 generic_acmg_combination_rules
PM4	N/A	Not applicable: an intronic substitution with no protein length change, not an in-frame indel or stop-loss variant.	final_classification_framework generic_acmg_combination_rules pvs1_variant_assessment
PM5	N/A	Not applicable: no amino acid change (p.?), so no same-residue missense comparison is possible.	pm5_candidates generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo observation of the variant was reported in ClinVar or the literature.
PP1	Not assessed	Not assessed: no affected family members were tested, so no segregation data existed.
PP2	N/A	Not applicable: applies to missense variants only; this variant is intronic and non-coding.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.08, below the >0.2 PP3 threshold for predicted 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 proband phenotype or family-history information was available to judge phenotype specificity.	clinvar
PP5	Not met	Not met: no expert-panel ClinVar classification exists; the only submission is a single-lab Likely benign record.	clinvar
BA1	Not met	Not met: absent from gnomAD (AF=0), far below the >1% BA1 population-frequency threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency 0, below the >0.3% threshold; no excess carrier frequency observed.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: no carriers observed in healthy individuals (AF=0); BS2 requires positive observation of the variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no well-established functional assay, such as an RNA splicing study, demonstrating normal function.	generic_acmg_combination_rules spliceai PMID:28492532 clinvar vcep_path_250_323 gnomad_v2 gnomad_v4
BS4	Not assessed	Not assessed: no family-testing data existed to observe a non-segregation event.
BP1	N/A	Not applicable: targets missense variants in truncation-driven genes; this variant is intronic and POLE missense is a major disease mechanism.	vcep_path_250_323 generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second POLE variant was observed, so no cis/trans configuration could be evaluated.	clinvar PMID:28492532 generic_acmg_combination_rules
BP3	N/A	Not applicable: an intronic substitution, not an in-frame indel in a repeat region.	final_classification_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.08, below the 0.1 threshold; no significant splice impact predicted.	spliceai generic_acmg_combination_rules final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no proband data on an alternate molecular basis for disease was available.	clinvar
BP6	Not met	Not met: no expert-panel ClinVar classification exists; the single-lab Likely benign label does not qualify.	clinvar
BP7	N/A	Not applicable: applies to synonymous coding variants; this is an intronic substitution.

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.