LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-25
Case ID: NM_006231.4_c.4275C_T_20260825_143858
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.4275C>T

POLE  · NP_006222.2:p.(Gly1425=)  · NM_006231.4
GRCh37: chr12:133220438 G>A  ·  GRCh38: chr12:132643852 G>A
Gene: POLE Transcript: NM_006231.4
Final call
VUS
PM2 supporting 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.(Gly1425=)
gnomAD AF
1.8587107238934784e-06 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): extremely rare in population databases (gnomAD v4.1 AF 1.86e-06, 0 homozygotes), below the 0.1% rarity threshold.
2
BP4 (Supporting): SpliceAI max delta 0.037 predicts no splice impact, below the <0.1 benign-splice threshold.
3
VUS: the single supporting pathogenic factor (PM2) conflicts with the single supporting benign factor (BP4), which does not reach any LP/LB or P/B combination.
Final determination: Only 1 Supporting pathogenic (PM2) + 1 Supporting benign (BP4) are met, insufficient for any Pathogenic/Likely Pathogenic or Benign/Likely Benign combination under the custom POLE framework's ACMG/AMP 2015 thresholds.
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: synonymous change creates no loss-of-function variant, and SpliceAI max delta 0.04 shows no splice impact.
pvs1_variant_assessment pvs1_generic_framework spliceai
PS1 N/A Not applicable: variant is synonymous, so there is no amino acid change to compare against known pathogenic missense changes.
PS2 Not assessed Not assessed: no parental testing or de novo confirmation was available for this variant.
PS3 Not assessed Not assessed: no functional assay data demonstrating an abnormal effect (e.g., polymerase activity or RNA studies) were available.
PS4 Not met Not met: variant is reported only three times in COSMIC, below the required combined count of 10 with TCGA recurrence.
vcep_path_250_323 vcep_path_250_323_s002
PM1 N/A Not applicable: variant lies outside the exonuclease-domain hotspot (approximately amino acids 268-471) and is synonymous.
vcep_path_250_323
PM2 Met Met (Supporting): extremely rare in gnomAD v4.1 at AF 1.86e-06 (3/1,614,022 alleles), below the 0.1% rarity threshold.
gnomad_v4 gnomad_v2 gnomad_canada
PM3 Not assessed Not assessed: no phase-resolved biallelic or in-trans genotype evidence was available.
PM4 N/A Not applicable: synonymous substitution does not alter protein length.
pvs1_variant_assessment
PM5 N/A Not applicable: no amino acid change, so there is no novel missense to compare at codon 1425.
pm5_candidates
PM6 Not assessed Not assessed: no de novo observation or parental testing was documented.
PP1 Not assessed Not assessed: no segregation or pedigree data were available.
PP2 N/A Not applicable: PP2 applies to missense variants only; this variant is synonymous.
PP3 Not met Not met: SpliceAI max delta 0.037 is below the >0.2 supporting-pathogenic splice threshold.
spliceai generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype or tumor characteristics were provided.
PP5 Not met Not met: the ClinVar Likely benign label rests on two single-submitter submissions, with no expert-panel review.
clinvar
BA1 Not met Not met: gnomAD v4.1 AF 1.86e-06 is far below the stand-alone benign high-frequency threshold.
gnomad_v4 gnomad_v2 gnomad_canada
BS1 Not met Not met: highest population AF 2.54e-06 (European non-Finnish) is below the benign frequency threshold.
gnomad_v4 gnomad_v2 gnomad_canada
BS2 Not met Not met: no homozygotes are reported in gnomAD v2.1 or v4.1, so no benign homozygote evidence exists.
gnomad_v4 gnomad_v2 gnomad_canada
BS3 Not assessed Not assessed: no functional data demonstrating normal protein function were available.
BS4 Not assessed Not assessed: no unaffected relatives or segregation data were documented.
BP1 N/A Not applicable: BP1 applies to missense variants; this variant is synonymous.
BP2 Not assessed Not assessed: no phase-resolved observation with a pathogenic variant was available.
BP3 N/A Not applicable: variant is a single-nucleotide substitution, not an in-frame indel.
pvs1_variant_assessment
BP4 Met Met (Supporting): SpliceAI max delta 0.037 is below the <0.1 benign-splice threshold.
spliceai generic_acmg_combination_rules
BP5 Not assessed Not assessed: no alternate molecular cause or phenotype data were provided.
BP6 Not met Not met: the ClinVar Likely benign label comes from two single-submitter laboratories, not an expert panel.
clinvar
BP7 N/A Not applicable: applying it would double-count the same SpliceAI evidence already used for BP4.
spliceai generic_acmg_combination_rules
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