LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-11
Case ID: NM_006231.4_c.3332G_A_20260811_154807
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.3332G>A

POLE  · NP_006222.2:p.(Arg1111Gln)  · NM_006231.4
GRCh37: chr12:133234500 C>T  ·  GRCh38: chr12:132657914 C>T
Gene: POLE Transcript: NM_006231.4
Final call
VUS
PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Arg1111Gln)
gnomAD AF
3.5312965805897636e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): extremely low population frequency — gnomAD total AFs 0.0024-0.0035%, highest subpopulation 0.0109%, zero homozygotes, all below the 0.1% threshold.
2
Overall: Uncertain Significance — a single Supporting criterion (PM2) satisfies no Pathogenic, Likely Pathogenic, or Benign combination.
Final determination: Under the governing León-Castillo et al. 2020 custom POLE framework (standard ACMG/AMP 2015 final-combination thresholds), a single Supporting-strength criterion (PM2_Supporting) with no other met pathogenic or benign criteria satisfies none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign combinations, so the variant defaults to 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 missense substitution is not a null variant (nonsense, frameshift, splice-site, or deletion), to which PVS1 is limited.
pvs1_variant_assessment pvs1_generic_framework spliceai pvs1_gene_context generic_acmg_combination_rules
PS1 Not met Not met: no source establishes p.Arg1111Gln as pathogenic — ClinVar classifies this exact variant as uncertain significance across three laboratories.
clinvar pm5_candidates vcep_path_250_323 PMID:25394175
PS2 Not assessed Not assessed: no de novo occurrence or parental-testing data was available for this variant.
clinvar
PS3 Not assessed Not assessed: insufficient functional-study evidence was available to evaluate this variant.
PS4 Not met Not met: the variant's somatic recurrence (n=4) falls below the required >=10 in both COSMIC and TCGA endometrial cohorts.
vcep_path_250_323 vcep_path_250_323_s002
PM1 Not met Not met: residue 1111 lies outside the exonuclease-domain hotspot region occupied by the framework's established pathogenic substitutions.
vcep_path_250_323 vcep_path_250_323_s002 clinvar oncokb
PM2 Met Met (Supporting): all population frequencies are far below the 0.1% threshold (highest subpopulation 0.0109%), with zero homozygotes.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no biallelic or trans-phase observation with a pathogenic variant was available.
clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules pm5_candidates PMID:25394175
PM4 Not met Not met: the substitution causes no protein length change (no in-frame indel or stop-loss).
pvs1_variant_assessment spliceai generic_acmg_combination_rules
PM5 Not met Not met: no pathogenic missense at residue 1111 with a different amino-acid change has been reported. Flagged for human review: other missense changes at residue 1111 were not exhaustively surveyed.
pm5_candidates clinvar vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PM6 Not assessed Not assessed: no de novo occurrence (assumed or confirmed) has been reported for this variant.
clinvar
PP1 Not assessed Not assessed: no family segregation data was available for this variant.
clinvar
PP2 Not assessed Not assessed: no gene-level missense-constraint metric (e.g., gnomAD Z-score) was available to evaluate this gene.
generic_acmg_combination_rules vcep_path_250_323
PP3 Not met Not met: REVEL score 0.36 is below the >=0.932 supporting threshold.
revel spliceai bayesdel vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype or family-history data was available.
clinvar
PP5 Not met Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.
clinvar
BA1 Not met Not met: highest allele frequency (0.0109%) is roughly two orders of magnitude below the >1% BA1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1 Not met Not met: highest allele frequency (0.0109%) is about 30-fold below the >0.3% BS1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2 Not met Not met: POLE cancer predisposition is adult-onset and incompletely penetrant, so the full-penetrance-at-early-age precondition is unmet.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3 Not assessed Not assessed: insufficient functional-study evidence was available.
BS4 Not assessed Not assessed: no family non-segregation data was available for this variant.
clinvar
BP1 Not met Not met: missense is an established POLE disease mechanism (five recurrent exonuclease-domain hotspots), so BP1 cannot apply.
generic_acmg_combination_rules vcep_path_250_323 oncokb
BP2 Not assessed Not assessed: no cis/trans phase data relative to a pathogenic variant was available.
clinvar generic_acmg_combination_rules PMID:25394175
BP3 N/A Not applicable: BP3 applies only to in-frame insertions/deletions, and this is a single-nucleotide substitution.
generic_acmg_combination_rules pvs1_variant_assessment
BP4 Not met Not met: REVEL score 0.36 is above the <=0.016 benign supporting threshold.
revel spliceai bayesdel vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules
BP5 Not assessed Not assessed: no data on an alternate molecular basis of disease was available.
BP6 Not met Not met: no expert-panel ClinVar classification exists; all three submissions are single-submitter laboratories reporting uncertain significance.
clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous variants, and this is a missense substitution.
spliceai generic_acmg_combination_rules
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