LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-13
Case ID: NM_006231.4_c.4039C_T_20261013_195335
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.4039C>T

POLE  · NP_006222.2:p.(Leu1347=)  · NM_006231.4
GRCh37: chr12:133225625 G>A  ·  GRCh38: chr12:132649039 G>A
Gene: POLE Transcript: NM_006231.4
Final call
VUS
PM2 supporting BP7 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Leu1347=)
gnomAD AF
1.8595379420121688e-06 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PM2 (supporting) is met because the gnomAD v4.1 all-comers allele frequency of 1.86e-06 is far below the 1e-4 rarity threshold.
2
VUS: BP7 (supporting) is met because this synonymous variant's SpliceAI maximum delta of 0.014 predicts no splicing impact.
3
VUS: one supporting pathogenic plus one supporting benign criterion is a conflicting combination that satisfies no classification rule.
Final determination: Under the local POLE framework, which retains ACMG/AMP 2015 final-combination thresholds, a single supporting pathogenic criterion (PM2) together with a single supporting benign criterion (BP7) satisfies no Pathogenic, Likely Pathogenic, Benign or Likely Benign combination and therefore yields 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.4039C>T is synonymous (p.Leu1347=) with SpliceAI max delta 0.014, so no null-variant consequence exists for PVS1.
pvs1_generic_framework pvs1_variant_assessment spliceai
PS1 N/A Not applicable: c.4039C>T is synonymous (p.Leu1347=), so it introduces no amino-acid change for PS1 to match against an established pathogenic variant.
clinvar vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PS2 Not assessed Not assessed: no proband, parental testing, parentage confirmation, or family-history data exist for this variant in the case evidence.
generic_acmg_combination_rules final_classification_framework
PS3 Not met Not met: no functional RNA/splice or protein assay exists for p.(Leu1347=); SpliceAI max delta 0.014 is in-silico and cannot support PS3.
vcep_path_250_323 final_classification_framework spliceai PMID:25394175 PMID:28492532
PS4 Not met Not met: this synonymous variant is absent from Supplementary Table S1, so its recurrence count of 0 fails the framework's combined EC count >=10 requirement.
vcep_path_250_323_s002 vcep_path_250_323
PM1 Not met Not met: p.Leu1347= is not one of the framework's enumerated exonuclease-domain hotspot substitutions and lies outside the exonuclease domain, whose hotspots span residues 286-459.
vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PM2 Met Met (supporting): gnomAD v4.1 frequency 1.86e-06 and group-maximum 2.80e-07 both fall below the 1e-4 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no trans/phase data - no second POLE variant or parental genotypes - so PM3's requirement for a pathogenic variant in trans cannot be evaluated.
clinvar final_classification_framework vcep_path_250_323
PM4 N/A Not applicable: c.4039C>T is synonymous (p.Leu1347=), producing no protein length change for PM4 to assess.
pvs1_variant_assessment spliceai
PM5 N/A Not applicable: c.4039C>T is synonymous (p.Leu1347=), so there is no missense change at residue 1347 for PM5 to compare with a pathogenic change.
pm5_candidates vcep_path_250_323_s002 clinvar final_classification_framework
PM6 Not assessed Not assessed: no proband or parent-of-origin data exist, so no assumed de novo occurrence can be documented for this variant.
generic_acmg_combination_rules final_classification_framework
PP1 Not assessed Not assessed: no pedigree, affected relatives, or meioses are available, so co-segregation of c.4039C>T with disease cannot be evaluated.
generic_acmg_combination_rules final_classification_framework
PP2 N/A Not applicable: PP2 applies only to a missense variant, and c.4039C>T is a synonymous change (p.Leu1347=).
vcep_path_250_323 clinvar final_classification_framework
PP3 Not met Not met: synonymous variant with SpliceAI max delta 0.014, far below the >=0.2 PP3 supporting threshold.
spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
PP4 Not assessed Not assessed: no proband phenotype or family-history data was recorded for this case, so phenotype specificity for a single-gene disorder could not be evaluated.
PP5 Not met Not met: ClinVar classifies this variant Likely benign from 2 single-submitter laboratories with 0 expert-panel submissions, failing the expert-panel pathogenic requirement.
clinvar
BA1 Not met Not met: the highest gnomAD frequency is 1.10e-05 (South Asian), far below the 0.05 BA1 stand-alone benign threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest gnomAD frequency, 1.10e-05, is well below the 0.01 BS1 strong benign threshold.
gnomad_v2 gnomad_v4
BS2 Not met Not met: zero homozygotes and only 3 carrier alleles in gnomAD, with no unaffected-adult evidence required by BS2.
gnomad_v2 gnomad_v4
BS3 Not met Not met: no experimental assay shows a non-damaging effect for p.(Leu1347=); SpliceAI max delta 0.014 is in-silico, and ClinVar status is not a functional dataset.
vcep_path_250_323 final_classification_framework spliceai PMID:25394175 PMID:28492532
BS4 Not assessed Not assessed: no family with genotyped affected and unaffected members exists, so non-segregation of c.4039C>T cannot be demonstrated.
generic_acmg_combination_rules final_classification_framework clinvar
BP1 N/A Not applicable: BP1 applies only to missense variants, and c.4039C>T is synonymous; POLE disease is additionally driven by missense, not truncating, variants.
vcep_path_250_323 clinvar final_classification_framework
BP2 Not assessed Not assessed: no co-occurring pathogenic variant and no phasing data, so BP2's in-trans-or-in-cis requirement for c.4039C>T is unevidenced.
clinvar final_classification_framework vcep_path_250_323
BP3 N/A Not applicable: c.4039C>T is a single-nucleotide synonymous change (p.Leu1347=) with no in-frame indel in a repeat region.
pvs1_variant_assessment spliceai
BP4 Not met Not met: the single SpliceAI max delta 0.014 supports no splice impact but is allocated to BP7, leaving no independent BP4 evidence.
spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
BP5 Not assessed Not assessed: no case-level genotype or co-occurring-variant data was available, so an alternate molecular basis for disease could not be evaluated.
BP6 Not met Not met: the ClinVar Likely benign classification carries 0 expert-panel submissions, so BP6's expert-panel benign-source requirement is not satisfied.
clinvar
BP7 Met Met, supporting: synonymous variant with SpliceAI max delta 0.014, far below the <=0.1 no-splice-impact threshold.
spliceai
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