LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-18
Case ID: NM_006231.4_c.6331-24C_T_20260918_224832
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.6331-24C>T

POLE  · NP_006222.2:p.?  · NM_006231.4
GRCh37: chr12:133202927 G>A  ·  GRCh38: chr12:132626341 G>A
Gene: POLE Transcript: NM_006231.4
Final call
VUS
BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.?
gnomAD AF
0.00012970329595313304 (v4.1)
ClinVar
Likely benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 supporting: SpliceAI max delta 0.076 is below the <=0.1 threshold, so no splice-altering effect is predicted for this intronic variant.
2
VUS: the single supporting benign criterion (BP4) does not satisfy the Likely Benign rule requiring a strong plus supporting benign criterion or two supporting benign criteria.
Final determination: Under the Leon-Castillo et al. 2020 custom POLE framework's standard ACMG/AMP 2015 combination logic, one supporting benign criterion (BP4) alone meets neither the Likely Benign rule (1 strong benign plus 1 supporting benign, or >=2 supporting benign) nor any pathogenic rule, so the call is 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 Not met Not met: the intronic c.6331-24C>T (24 bp from the exon 46 acceptor) has SpliceAI max delta 0.076, below the 0.2 supporting cutoff, so no null effect is predicted.
pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context spliceai PMID:25741868 final_classification_framework vcep_path_250_323
PS1 N/A Not applicable: c.6331-24C>T is intronic with predicted consequence p.?, so it produces no amino-acid change to match against an established pathogenic variant.
vcep_path_250_323 vcep_path_250_323_s002 PMID:25741868
PS2 Not assessed Not assessed: no proband or parental genotypes are available to establish a confirmed de novo occurrence.
final_classification_framework vcep_path_250_323 PMID:25741868 clinvar
PS3 Not assessed Not assessed: no functional or RNA assay of POLE c.6331-24C>T exists; SpliceAI 0.076 and the absent REVEL score are in-silico only.
vcep_path_250_323 spliceai clinvar PMID:25741868
PS4 Not met Not met: intronic c.6331-24C>T is absent from the POLE recurrent-variant table (Supplementary Table S1) and no case-control enrichment statistic exists.
vcep_path_250_323_s002 vcep_path_250_323 clinvar gnomad_v2 gnomad_v4
PM1 Not met Not met: c.6331-24C>T is intronic (intron 45, p.?) and outside every POLE exonuclease-domain hotspot (P286R, V411L, S297F, A456P, S459F).
vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001 final_classification_framework spliceai PMID:25741868
PM2 Not met Not met: total allele frequency 0.000237 (gnomAD v2.1, 66/278,448 alleles) exceeds the 0.0001 PM2 rarity threshold in all four datasets.
gnomad_v2 gnomad_v4 PMID:25741868 final_classification_framework
PM3 Not assessed Not assessed: no second POLE variant, zygosity or phase is documented and gnomAD reports zero homozygotes in v2.1 (66/278,448) and v4.1 (209/1,611,370) alleles, leaving an in-trans configuration untested.
clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 PMID:25741868 pvs1_gene_context vcep_path_250_323
PM4 N/A Not applicable: variant is an intronic substitution with no in-frame indel or stop-loss, so no protein-length change exists to score (SpliceAI max delta 0.076).
PMID:25741868 spliceai pvs1_variant_assessment
PM5 N/A Not applicable: c.6331-24C>T alters no codon (p.?), so there is no residue at which a different pathogenic missense could be compared.
pm5_candidates vcep_path_250_323_s002 PMID:25741868
PM6 Not assessed Not assessed: no proband carrying the variant is documented, so no assumed de novo occurrence can be recorded.
final_classification_framework vcep_path_250_323 PMID:25741868 clinvar
PP1 Not assessed Not assessed: no pedigree or affected-relative genotypes provide any co-segregation data for this variant.
final_classification_framework vcep_path_250_323 PMID:25741868 clinvar
PP2 N/A Not applicable: c.6331-24C>T is intronic with no amino-acid substitution (p.?), so the missense-specific PP2 criterion cannot apply.
vcep_path_250_323_s002 PMID:25741868
PP3 Not met Not met: SpliceAI max delta 0.076 vs the >=0.2 supporting threshold for PP3.
spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 PMID:25741868
PP4 Not assessed Not assessed: no phenotype or family-history data for the proband were available, so disease specificity could not be evaluated.
clinvar vcep_path_250_323
PP5 Not met Not met: the only ClinVar record for this exact variant is a single-submitter, 1-star laboratory assertion, not an expert-panel pathogenic classification.
clinvar
BA1 Not met Not met: highest population frequency 0.00053 (gnomAD v2.1 non-cancer exomes, non-Finnish European) versus the BA1 stand-alone threshold of 0.05.
gnomad_v2 gnomad_v4 PMID:25741868 final_classification_framework
BS1 Not met Not met: highest observed frequency 0.00053 versus the generic BS1 threshold of 0.01, about 19-fold below and 8/8 dataset values under 0.001.
gnomad_v2 gnomad_v4 PMID:25741868 final_classification_framework
BS2 N/A Not applicable: BS2 needs a disorder fully penetrant at an early age, which adult-onset POLE cancer predisposition is not, and no homozygotes exist in any dataset.
gnomad_v2 gnomad_v4 PMID:25741868 final_classification_framework
BS3 Not assessed Not assessed: no functional assay demonstrates preserved POLE splicing or proofreading; SpliceAI 0.076 and the absent REVEL score are in-silico only.
vcep_path_250_323 spliceai clinvar PMID:25741868
BS4 Not assessed Not assessed: no affected family members were genotyped, so lack of segregation cannot be demonstrated for this variant.
final_classification_framework vcep_path_250_323 PMID:25741868 clinvar gnomad_v2 gnomad_v4
BP1 N/A Not applicable: BP1 is limited to missense variants, and c.6331-24C>T is intronic with no amino-acid substitution (p.?).
vcep_path_250_323 vcep_path_250_323_s002 PMID:25741868
BP2 Not assessed Not assessed: no documented co-occurring pathogenic POLE allele and no phase data, with zero homozygotes reported in gnomAD v2.1 (66/278,448) and v4.1 (209/1,611,370) alleles, so no cis or trans configuration can be evaluated.
clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 PMID:25741868 pvs1_gene_context vcep_path_250_323
BP3 N/A Not applicable: this is a single-nucleotide intronic substitution, not an in-frame indel, so BP3's repetitive-region length-change premise is absent (SpliceAI max delta 0.076).
PMID:25741868 spliceai pvs1_variant_assessment
BP4 Met Met at supporting: SpliceAI max delta 0.076, at or below the <=0.1 BP4 threshold.
spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 PMID:25741868
BP5 Not assessed Not assessed: no case-level data were available to determine whether the variant co-occurs with an alternate molecular basis for disease.
clinvar
BP6 Not met Not met: the exact-variant ClinVar Likely benign label comes from one non-expert laboratory (1 star, zero expert-panel submissions), which cannot trigger BP6.
clinvar
BP7 N/A Not applicable: c.6331-24C>T is intronic, not a synonymous coding variant, so BP7 is out of scope.
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