LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-29
Case ID: NM_006231.4_c.2173_23G_T_20260929_220234
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.2173+23G>T

POLE  · NP_006222.2:p.?  · NM_006231.4
GRCh37: chr12:133244919 C>A  ·  GRCh38: chr12:132668333 C>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
0.0003008641595084721 (v4.1)
ClinVar
Likely benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 supporting: the deep-intronic change has SpliceAI max delta 0.003, below the 0.1 no-impact cutoff, so no splice effect is predicted.
Final determination: Under the governing framework's retained ACMG/AMP 2015 combination logic, a single supporting benign criterion (BP4) with no pathogenic criteria met does not reach any benign or likely benign category and 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 Not met Not met: this deep-intronic substitution (23 bp into intron 19) has SpliceAI max delta 0.003, so no null consequence is predicted and PVS1 cannot be triggered.
spliceai pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context final_classification_framework vcep_path_250_323 generic_acmg_combination_rules
PS1 N/A Not applicable: this intronic variant (c.2173+23G>T, p.?) produces no amino-acid change, so there is no same-residue comparator for PS1.
vcep_path_250_323 vcep_path_250_323_s002
PS2 Not assessed Not assessed: no proband or parental genotype data exist in this case to establish de novo occurrence.
PS3 Not assessed Not assessed: no functional or RNA assay of POLE c.2173+23G>T exists; the only splice datum is computational (SpliceAI max delta 0.003).
vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 final_classification_framework generic_acmg_combination_rules spliceai clinvar oncokb
PS4 Not met Not met: variant recurrence count 0 in the COSMIC/TCGA EC table vs the PS4_Supporting requirement of combined count >=10.
vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PM1 Not met Not met: intronic c.2173+23G>T (intron 19, p.?) lies outside the POLE exonuclease domain and all framework hotspots, and is present in gnomAD at 0.066% overall.
vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework gnomad_v2 gnomad_v4
PM2 Not met Not met: total allele frequency 0.000665 (gnomAD v2.1, 155/233,160 alleles) exceeds the 0.0001 PM2 rarity threshold in every dataset assessed.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
PM3 Not assessed Not assessed: no phase, pedigree, or second-variant data exist to determine whether a pathogenic POLE allele is in trans.
clinvar gnomad_v4 pvs1_gene_context final_classification_framework
PM4 N/A Not applicable: c.2173+23G>T is intronic with SpliceAI max delta 0.003, so no in-frame indel, stop-loss or protein-length change exists to score.
generic_acmg_combination_rules spliceai pvs1_variant_assessment final_classification_framework
PM5 N/A Not applicable: c.2173+23G>T is intronic (p.?) with no affected residue, so no same-residue pathogenic missense comparator can exist for PM5.
pm5_candidates
PM6 Not assessed Not assessed: no proband or parental testing data are available to support an assumed de novo occurrence.
PP1 Not assessed Not assessed: no pedigree or relative genotype data are available to assess co-segregation.
PP2 N/A Not applicable: this intronic change (c.2173+23G>T, p.?) is not a missense variant, so a missense-mechanism criterion such as PP2 cannot apply.
vcep_path_250_323_s002
PP3 Not met Not met: SpliceAI max delta 0.003 for this intronic variant, far below the >=0.2 supporting PP3 threshold.
spliceai vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
PP4 Not assessed Not assessed: no proband phenotype, HPO terms, or family history anywhere in the case, so PP4's patient-specific specificity requirement cannot be evaluated.
PP5 Not met Not met: no ClinVar expert-panel assertion exists (0 expert-panel submissions); the sole record is Likely benign, single submitter.
clinvar
BA1 Not met Not met: highest ancestry frequency 0.59% (gnomAD v2.1 African/African American, 144/24,282 alleles) versus the 0.05 BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
BS1 Not met Not met: highest ancestry frequency 0.98% (gnomAD-Canada African/African American) falls just under the generic 0.01 BS1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
BS2 Not met Not met: three homozygous carriers (gnomAD v4.1, gnomAD-Canada) but POLE disease evaluated here is adult-onset and incompletely penetrant, failing BS2's early-onset premise.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
BS3 Not assessed Not assessed: no assay demonstrates preserved POLE splicing or proofreading; SpliceAI max delta 0.003 is in-silico only, not functional evidence.
vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 final_classification_framework generic_acmg_combination_rules spliceai clinvar oncokb
BS4 Not assessed Not assessed: no pedigree with affected relatives and genotypes exists to assess non-segregation.
BP1 N/A Not applicable: c.2173+23G>T is intronic (p.?) and not a missense variant, so a truncating-only-mechanism criterion such as BP1 does not apply.
vcep_path_250_323
BP2 Not assessed Not assessed: no phase or companion-variant data exist to place this allele in cis or trans with a pathogenic POLE variant.
clinvar gnomad_v4 pvs1_gene_context final_classification_framework
BP3 N/A Not applicable: c.2173+23G>T is a single-nucleotide intronic substitution, not an in-frame indel, so BP3's repetitive-region length-change premise is absent (SpliceAI max delta 0.003).
generic_acmg_combination_rules spliceai pvs1_variant_assessment vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
BP4 Met Met at supporting: SpliceAI max delta 0.003 for this intronic variant, below the <=0.1 BP4 threshold.
spliceai vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004
BP5 Not assessed Not assessed: the case contains no proband genotype or molecular diagnosis, so BP5's alternate-molecular-basis requirement cannot be evaluated.
BP6 Not met Not met: 0 expert-panel ClinVar submissions for this variant, so the single-submitter Likely benign label cannot satisfy BP6.
clinvar
BP7 N/A Not applicable: BP7 covers synonymous variants only, and this substitution is intronic (c.2173+23G>T), not a synonymous coding change.
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