NM_006231.4:c.547G>A

POLE · NP_006222.2:p.(Ala183Thr) · NM_006231.4

GRCh37: chr12:133256114 C>T · GRCh38: chr12:132679528 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting PP2 supporting BP4 moderate

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ala183Thr)

gnomAD AF

3.841844878696846e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

VUS: PM2 (supporting) is met because gnomAD v4.1 frequency 0.0000384 (62/1,613,808 alleles, no homozygotes) is below the 0.0001 rarity threshold.

VUS: PP2 (supporting) is met because POLE germline disease is caused by missense proofreading-domain substitutions and this is a missense change.

VUS: BP4 (moderate) is met because REVEL 0.037 falls inside the moderate benign band (<=0.183).

Final determination: Under the Leon-Castillo et al. 2020 custom POLE framework, which customizes individual criteria but retains ACMG/AMP 2015 final combination logic, two supporting pathogenic criteria (PM2 and PP2) satisfy no pathogenic or likely pathogenic rule and the single moderate benign criterion (BP4) satisfies no benign or likely benign rule, so the variant is classified as a Variant of 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.547G>A is a missense substitution (p.Ala183Thr) with no truncating or canonical splice-site consequence, so PVS1's null-variant scope excludes it.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework final_classification_framework PMID:25741868
PS1	Not met	Not met: the governing POLE pathogenic set is p.P286R, p.V411L, p.S297F, p.A456P and p.S459F, and ClinVar records no pathogenic p.Ala183Thr change.	PMID:25741868 clinvar final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PS2	Not assessed	Not assessed: no confirmed de novo occurrence for c.547G>A, since no parental testing or proband data exists in any available source.	clinvar final_classification_framework
PS3	Not assessed	Not assessed: no functional assay data exist for POLE p.Ala183Thr; the only retrieved functional claims are in-silico (REVEL 0.037), which cannot establish PS3.	oncokb clinvar final_classification_framework vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 PMID:25741868
PS4	Not met	Not met: A183T is absent from Supplementary Table S1 (combined endometrial-cancer recurrence count 0, not >=10), so the POLE custom PS4 rule cannot fire.	vcep_path_250_323_s002 vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004 clinvar oncokb PMID:25741868
PM1	Not met	Not met: p.Ala183Thr lies outside the POLE exonuclease/proofreading domain, where the hotspots (p.P286R-p.S459F) and all framework domain variants are located.	PMID:25741868 final_classification_framework vcep_path_250_323 vcep_path_250_323_s002 oncokb pvs1_gene_context
PM2	Met	Met at Supporting: gnomAD v4.1 frequency 0.0000384 (62/1,613,808; grpmax FAF 0.0000378) is below the 0.0001 Supporting PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada clinvar vcep_path_250_323 final_classification_framework PMID:25741868
PM3	Not assessed	Not assessed: no second POLE variant or phasing data exist, and gnomAD shows 2/251,408 alleles with zero homozygotes, so in-trans configuration is untested.	clinvar final_classification_framework gnomad_v2 gnomad_v4 pvs1_gene_context
PM4	N/A	Not applicable: p.Ala183Thr is a single amino-acid substitution with no in-frame indel or stop-loss, so PM4's protein-length-change scope excludes it.	pvs1_variant_assessment final_classification_framework PMID:25741868
PM5	Not met	Not met: no pathogenic missense change at POLE residue 183 is reported, and same-residue candidate harvesting returned zero comparators.	PMID:25741868 clinvar pm5_candidates vcep_path_250_323_s002
PM6	Not assessed	Not assessed: no assumed de novo report for c.547G>A exists, as no proband, parental samples or family data were available.	clinvar final_classification_framework
PP1	Not assessed	Not assessed: no pedigree, affected relatives or meioses are reported for c.547G>A, so co-segregation cannot be evaluated.	clinvar final_classification_framework
PP2	Met	Met at supporting: missense exonuclease-domain substitutions are the established POLE disease mechanism, though no gnomAD missense-constraint metric was available to confirm rare benign missense variation.	PMID:25741868 oncokb pvs1_gene_context vcep_path_250_323
PP3	Not met	Not met: REVEL 0.037 is far below the 0.644 supporting PP3 threshold, and no splice prediction was available.	vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323 revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype, HPO terms, or family history were captured, so phenotype specificity for POLE cannot be evaluated.	clinvar
PP5	Not met	Not met: ClinVar 540667 has zero expert-panel submissions (1-star, conflicting: 3 uncertain, 1 likely benign), so no expert-panel pathogenic assertion supports PP5.	clinvar oncokb
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.0000384 (62/1,613,808 alleles) is roughly 1,300-fold below the 0.05 stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada vcep_path_250_323 final_classification_framework PMID:25741868
BS1	Not met	Not met: the highest adequately powered population frequency, 0.0000483 in European (non-Finnish), is about 200-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada vcep_path_250_323 final_classification_framework PMID:25741868
BS2	Not met	Not met: zero homozygotes in every gnomAD cohort, and POLE cancer predisposition is adult-onset and incompletely penetrant, failing BS2's fully-penetrant-early premise.	gnomad_v2 gnomad_v4 gnomad_canada vcep_path_250_323 final_classification_framework PMID:25741868
BS3	Not assessed	Not assessed: no functional assay of POLE p.Ala183Thr shows a non-damaging effect; the benign-leaning in-silico REVEL 0.037 supports BP4, not BS3.	revel bayesdel oncokb clinvar final_classification_framework vcep_path_250_323 PMID:25741868
BS4	Not assessed	Not assessed: no family with multiple affected members is reported for c.547G>A, so non-segregation cannot be demonstrated.	clinvar final_classification_framework
BP1	Not met	Not met: POLE disease is caused by missense proofreading-domain substitutions such as p.P286R and p.V411L, so BP1's truncating-only premise fails.	PMID:25741868 oncokb pvs1_gene_context vcep_path_250_323
BP2	Not assessed	Not assessed: no data place this variant in cis or trans with a pathogenic POLE variant, and gnomAD reports zero homozygotes in every dataset.	clinvar final_classification_framework gnomad_v2 gnomad_v4 pvs1_gene_context
BP3	N/A	Not applicable: p.Ala183Thr is a single substitution, not an in-frame indel, and lies in no repetitive region, so BP3's scope excludes it.	pvs1_variant_assessment final_classification_framework PMID:25741868
BP4	Met	Met at moderate strength: REVEL 0.037 falls below the 0.183 moderate BP4 threshold.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel vcep_path_250_323 PMID:25741868
BP5	Not assessed	Not assessed: no case-level genotype or co-occurring alternate genetic cause was captured, so BP5 cannot be evaluated.	clinvar
BP6	Not met	Not met: ClinVar 540667 has no expert-panel submission, and the single Likely benign laboratory call is excluded from triggering BP6.	clinvar
BP7	N/A	Not applicable: p.(Ala183Thr) is a missense change, and BP7 applies only to synonymous variants.	PMID:25741868

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