NM_006231.4:c.4501G>A

POLE · NP_006222.2:p.(Gly1501Arg) · NM_006231.4

GRCh37: chr12:133219860 C>T · GRCh38: chr12:132643274 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Gly1501Arg)

gnomAD AF

9.295027903673766e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): ultra-rare population frequency — gnomAD v4.1 total AF 9.3e-06 with 0 homozygotes, far below the 0.1% cap.

Final classification: Uncertain Significance (VUS) — the single PM2_Supporting criterion satisfies no pathogenic or benign combination rule under ACMG/AMP 2015.

Final determination: Under the governing local custom POLE gene framework (Leon-Castillo et al. 2020, which uses standard ACMG/AMP 2015 combination logic for criteria it does not customize) and generic ACMG/AMP 2015 rules (PMID 25741868), the single met criterion PM2_Supporting satisfies no Pathogenic (e.g., PVS1+1PS, 2PS, 1PS+3PM), Likely Pathogenic (e.g., 3PM, 2PM+2PP, 1PM+4PP), Benign (BA1, 2BS), or Likely Benign (1BS+1BP, 2BP) combination; therefore the variant is Uncertain Significance.

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: this is a missense substitution, not a null variant, so the loss-of-function criterion does not apply.	pvs1_generic_framework pvs1_variant_assessment spliceai generic_acmg_combination_rules
PS1	Not met	Not met: no pathogenic record of p.Gly1501Arg via a different nucleotide change exists; ClinVar classifies this variant as Uncertain significance.	clinvar oncokb vcep_path_250_323
PS2	Not assessed	Not assessed: no de novo occurrence of this variant in a tested proband is documented in any source.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PS3	Not assessed	Not assessed: no variant-specific functional study of p.Gly1501Arg exists; OncoKB reports no functional evidence.	oncokb clinvar spliceai revel vcep_path_250_323 PMID:25394175 generic_acmg_combination_rules
PS4	Not met	Not met: the variant is absent from the Leon-Castillo recurrent-variant table and COSMIC, failing the somatic-recurrence rule.	vcep_path_250_323 vcep_path_250_323_s002 clinvar PMID:25394175
PM1	Not met	Not met: residue 1501 lies outside the exonuclease proofreading domain (residues 286-459) containing all established hotspots.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 clinvar
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency 9.3e-06, far below the 0.1% PM2 cap, with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules clinvar
PM3	Not assessed	Not assessed: no proband genotyping or phase data exist to test for a variant in trans with a pathogenic allele.	clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
PM4	N/A	Not applicable: single-nucleotide missense with no protein length change, so the in-frame indel/stop-loss criterion does not apply.	generic_acmg_combination_rules pvs1_variant_assessment spliceai
PM5	Not assessed	Not assessed: no pathogenic comparator at residue 1501 was found, though its absence is not comprehensively confirmed.	pm5_candidates clinvar vcep_path_250_323_s002
PM6	Not assessed	Not assessed: no de novo occurrence is documented with or without parentage confirmation.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PP1	Not assessed	Not assessed: no segregation or family-testing data document any informative meiosis.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PP2	Not assessed	Not assessed: no gene-level missense constraint data (e.g., gnomAD Z-score) are available to evaluate this rule.
PP3	Not met	Not met: REVEL 0.492 falls below the supporting threshold of 0.644, and SpliceAI max delta 0.01 shows no splice impact.	revel spliceai bayesdel vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no phenotype or family-history data for any carrier are available.	clinvar
PP5	Not met	Not met: ClinVar classifies this variant as Uncertain significance with no expert-panel submission.	clinvar PMID:25394175
BA1	Not met	Not met: highest observed allele frequency 0.00534% is roughly 300-fold below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v4.1 frequency 0.00093% is about 1,000-fold below the 1% threshold and 60-100x below the 0.3% convention.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1 and v4.1, and reference cohorts are not cancer-screened.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no well-established functional study shows a lack of damaging effect for p.Gly1501Arg.	oncokb clinvar spliceai revel vcep_path_250_323 PMID:25394175 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no affected relative has been tested and shown not to carry the variant.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
BP1	Not met	Not met: missense in the POLE exonuclease domain is an established disease mechanism, not primarily truncating variants.	vcep_path_250_323 oncokb
BP2	Not assessed	Not assessed: no second POLE variant or phase data exist to establish cis/trans configuration.	clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame insertion/deletion.	generic_acmg_combination_rules pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.492 is far above the benign supporting threshold of 0.016.	revel spliceai bayesdel vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no case-level information documents an alternate molecular basis in a carrier.
BP6	Not met	Not met: ClinVar classifies this variant as Uncertain significance with no expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: the variant is missense, not a synonymous change.	spliceai vcep_path_250_323

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