Variant classification summary

NM_006231.4:c.6634A>G

POLE · NP_006222.2:p.(Met2212Val) · NM_006231.4

GRCh37: chr12:133202254 T>C · GRCh38: chr12:132625668 T>C

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting PP2 supporting BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Met2212Val)

gnomAD AF

1.2393647016539322e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 total allele frequency 1.23936e-06 (2/1,613,730 alleles) sits far below the 0.0001 rarity threshold.

2

PP2 supporting: POLE pathogenicity is driven by exonuclease-domain missense substitutions, so missense is an established disease mechanism for this gene.

3

BP4 supporting: REVEL 0.212 falls in the benign computational band (<=0.29) for this missense substitution.

4

VUS: two supporting pathogenic criteria (PM2, PP2) conflict with one supporting benign criterion (BP4), and no combination rule reaches Likely Pathogenic or Likely Benign.

Final determination: Under the governing framework's retained ACMG/AMP 2015 combination logic, two supporting pathogenic criteria do not reach Likely Pathogenic (which requires at least one moderate criterion or a strong criterion) and one supporting benign criterion does not reach Likely Benign (which requires two), so the conflicting evidence falls into 'all other combinations', giving 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: c.6634A>G is a missense substitution (p.Met2212Val) with an unchanged protein length and SpliceAI max delta 0.014, so no null-variant consequence for PVS1 exists.	pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context spliceai final_classification_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic source reports the same p.Met2212Val change; ClinVar lists it only once as Uncertain significance.	clinvar vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PS2	Not assessed	Not assessed: no proband, pedigree, or parental genotype data exist to confirm or exclude a de novo occurrence.	final_classification_framework generic_acmg_combination_rules vcep_path_250_323
PS3	Not assessed	Not assessed: no functional assay of POLE p.Met2212Val exists; the only 'functional' data are in-silico predictor outputs.	oncokb clinvar final_classification_framework generic_acmg_combination_rules vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PS4	Not met	Not met: c.6634A>G (p.Met2212Val) has no row in Supplementary Table S1 and no COSMIC record, failing the >=10 EC-count PS4_Supporting rule.	vcep_path_250_323_s002 vcep_path_250_323 final_classification_framework generic_acmg_combination_rules
PM1	Not met	Not met: residue 2212 lies outside POLE's exonuclease domain and is absent from the five established hotspots (P286R, V411L, S297F, A456P, S459F).	vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PM2	Met	Met at supporting: gnomAD v4.1 total allele frequency 1.24e-06 versus the 0.0001 PM2 supporting rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
PM3	Not assessed	Not assessed: no phased POLE genotype, no trans partner, and zero homozygotes in gnomAD v4.1 (2/1,613,730 alleles) leave the in-trans configuration untested.	clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 pvs1_gene_context vcep_path_250_323
PM4	N/A	Not applicable: the c.6634A>G substitution changes one residue (p.Met2212Val) with no protein-length change, and SpliceAI max delta 0.014 excludes an in-frame splice product.	pvs1_variant_assessment spliceai final_classification_framework clinvar generic_acmg_combination_rules
PM5	Not met	Not met: no pathogenic missense variant is reported at residue M2212 (0 same-residue candidates; the ClinVar entry is Uncertain significance).	clinvar pm5_candidates vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PM6	Not assessed	Not assessed: no affected proband or any parental testing is documented, so an assumed de novo occurrence cannot be established.	final_classification_framework generic_acmg_combination_rules vcep_path_250_323
PP1	Not assessed	Not assessed: no pedigree or genotyped family members exist, so there are no meioses available to assess co-segregation.	final_classification_framework generic_acmg_combination_rules vcep_path_250_323
PP2	Met	Met at supporting: POLE pathogenicity is driven by exonuclease-domain missense substitutions, so missense is an established disease mechanism for this gene.	vcep_path_250_323 vcep_path_250_323_s003
PP3	Not met	Not met: REVEL 0.212 sits below the >=0.644 ClinGen SVI supporting PP3 threshold for this missense variant.	revel vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323
PP4	Not assessed	Not assessed: no proband phenotype, HPO terms, or family history were available to judge specificity for POLE-related disease.
PP5	Not met	Not met: the only ClinVar record (1478557) is Uncertain significance from a single non-expert submitter, with no expert-panel Pathogenic assertion.	clinvar oncokb final_classification_framework
BA1	Not met	Not met: highest observed allele frequency 1.69e-06 (gnomAD v4.1, European non-Finnish) versus the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework
BS1	Not met	Not met: highest observed allele frequency 1.69e-06 versus the 0.01 BS1 strong benign threshold, roughly 6,000-fold below.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework
BS2	N/A	Not applicable: BS2 requires a disorder fully penetrant at an early age, which adult-onset POLE cancer predisposition is not, and no homozygotes are observed.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework
BS3	Not assessed	Not assessed: no functional assay of POLE p.Met2212Val exists, so no non-damaging functional result is available for BS3.	oncokb clinvar final_classification_framework generic_acmg_combination_rules vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
BS4	Not assessed	Not assessed: no pedigree or family genotypes exist for this variant, so non-segregation with disease cannot be evaluated.	final_classification_framework generic_acmg_combination_rules vcep_path_250_323
BP1	Not met	Not met: POLE missense variants are an established pathogenic mechanism, so the gene is not a truncating-only (loss-of-function) disease gene.	vcep_path_250_323
BP2	Not assessed	Not assessed: no co-occurring pathogenic POLE allele or phase data, with zero homozygotes in gnomAD v4.1 (2/1,613,730 alleles), so no cis/trans configuration is testable.	clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 pvs1_gene_context vcep_path_250_323
BP3	N/A	Not applicable: c.6634A>G is a single-base substitution (p.Met2212Val), not an in-frame indel in a repeat region, with SpliceAI max delta 0.014 excluding cryptic indels.	pvs1_variant_assessment spliceai final_classification_framework vcep_path_250_323 generic_acmg_combination_rules
BP4	Met	Met at supporting: REVEL 0.212 falls in the ClinGen SVI BP4 band (<=0.29) but above the moderate cut-off (<=0.183).	revel vcep_path_250_323_s003 vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no case-level clinical or molecular data were available to determine whether an alternate molecular basis for disease exists.
BP6	Not met	Not met: ClinVar 1478557 is Uncertain significance from one non-expert laboratory, not a Benign/Likely benign expert-panel assertion.	clinvar oncokb final_classification_framework
BP7	N/A	Not applicable: p.Met2212Val is a missense substitution, and BP7 applies only to synonymous variants.

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