LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-10
Case ID: NM_006231.4_c.2284C_T_20260810_152303
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.2284C>T

POLE  · NP_006222.2:p.(Arg762Trp)  · NM_006231.4
GRCh37: chr12:133244124 G>A  ·  GRCh38: chr12:132667538 G>A
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.(Arg762Trp)
gnomAD AF
4.337367911656491e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): gnomAD allele frequency 0.0008% (v2.1) and 0.00043% (v4.1) with zero homozygotes, well below the 0.1% population-frequency threshold.
2
With only PM2 (Supporting) met, no ACMG/AMP 2015 pathogenic, likely-pathogenic, or benign combination is satisfied, yielding Uncertain Significance (VUS).
Final determination: Under the governing local custom POLE framework (Leon-Castillo et al. 2020, which retains standard ACMG/AMP 2015 final combination logic), only PM2 at Supporting strength is met; no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination is satisfied, so all remaining combinations resolve to 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 N/A Not applicable: this is a missense change, and PVS1 applies only to null variants such as nonsense, frameshift, or splice-site changes.
pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai clinvar
PS1 Not met Not met: no source establishes any Arg762 substitution as pathogenic, and no alternative nucleotide change at this codon produces Trp.
clinvar oncokb vcep_path_250_323 PMID:25394175 PMID:28492532
PS2 Not assessed Not assessed: no proband-parent trio or de novo occurrence data were available.
clinvar PMID:28492532 PMID:25394175 generic_acmg_combination_rules
PS3 Not assessed Not assessed: no functional assay evidence for this variant was available. Flagged for human review: a laboratory submission cites published functional studies without a PMID, which could not be verified.
oncokb clinvar generic_acmg_combination_rules
PS4 Not met Not met: the variant is absent from the framework's recurrent-variant table and has only a single somatic COSMIC occurrence (n=1), which is not recurrence.
vcep_path_250_323_s002 vcep_path_250_323 clinvar
PM1 Not met Not met: Arg762 lies outside the framework's exonuclease-domain hotspot region (residues 286-459) and in none of its hotspot lists.
vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 oncokb
PM2 Met Met (Supporting): gnomAD allele frequency 0.0008% (v2.1) and 0.00043% (v4.1) with zero homozygotes, below the 0.1% PM2 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no phase, pedigree, or proband genotype data were available to evaluate a trans arrangement.
clinvar generic_acmg_combination_rules PMID:25394175 PMID:28492532
PM4 N/A Not applicable: this missense change preserves the reading frame and protein length.
generic_acmg_combination_rules clinvar
PM5 Not assessed Not assessed: no pathogenic comparator missense at Arg762 was identified; the required same-residue survey is pending human review.
pm5_candidates clinvar PMID:25394175 PMID:28492532
PM6 Not assessed Not assessed: no evidence of a de novo occurrence, with or without confirmed parentage, was available.
clinvar PMID:28492532 PMID:25394175 generic_acmg_combination_rules
PP1 Not assessed Not assessed: no family segregation data were available.
clinvar PMID:28492532 PMID:25394175 generic_acmg_combination_rules
PP2 Not assessed Not assessed: no gene-level missense constraint metric (e.g., gnomAD Z-score) was available to establish a low rate of benign missense variation.
vcep_path_250_323 pvs1_gene_context gnomad_v2 gnomad_v4
PP3 Not met Not met: REVEL 0.552 falls in the indeterminate range (PP3 requires >=0.932), and SpliceAI max delta 0.00 shows no splice impact.
spliceai revel bayesdel final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004
PP4 Not assessed Not assessed: no proband phenotype or family-history data were available to establish phenotype specificity.
clinvar
PP5 Not met Not met: ClinVar lists only Uncertain significance from three clinical laboratories, with no expert-panel pathogenic classification.
clinvar
BA1 Not met Not met: the highest observed allele frequency is 0.00327%, versus the >1% BA1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1 Not met Not met: the highest allele frequency, 0.00327%, is about 100-fold below the >0.3% BS1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2 Not met Not met: no homozygotes and only 7 ultra-rare heterozygous carriers in 1.6 million gnomAD alleles, contrary to BS2's expected healthy-adult enrichment.
gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no functional assay evidence showing a lack of damaging effect was available.
oncokb generic_acmg_combination_rules
BS4 Not assessed Not assessed: no segregation data were available to test for lack of segregation in affected family members.
clinvar PMID:28492532 PMID:25394175 generic_acmg_combination_rules
BP1 Not met Not met: POLE disease is driven by missense rather than truncating variants, so a missense change cannot receive BP1.
vcep_path_250_323 pvs1_gene_context
BP2 Not assessed Not assessed: no phase data relative to another variant were available.
clinvar generic_acmg_combination_rules PMID:25394175 PMID:28492532
BP3 N/A Not applicable: the variant is a single-nucleotide substitution, not an in-frame indel in a repeat region.
generic_acmg_combination_rules clinvar
BP4 Not met Not met: REVEL 0.552 is far above the <=0.016 BP4 threshold, and SpliceAI shows no splice impact.
spliceai revel bayesdel final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004
BP5 Not assessed Not assessed: no case-level data on an alternate molecular basis of disease were available.
BP6 Not met Not met: no expert-panel Benign/Likely benign classification exists; ClinVar shows only Uncertain significance.
clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous variants, and this is a missense change.
spliceai
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