LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-15
Case ID: NM_006231.4_c.2792T_C_20260915_185508
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.2792T>C

POLE  · NP_006222.2:p.(Phe931Ser)  · NM_006231.4
GRCh37: chr12:133238185 A>G  ·  GRCh38: chr12:132661599 A>G
Gene: POLE Transcript: NM_006231.4
Final call
VUS
PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Phe931Ser)
gnomAD AF
1.6727878310261253e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 supporting: gnomAD v4.1 all-comers allele frequency is 1.67e-05, below the 0.0001 threshold, with no homozygotes.
2
PP3 supporting: REVEL 0.749 places this missense change in the PP3 supporting band under the generic in-silico fallback.
Final determination: Two supporting pathogenic criteria (PM2 and PP3) match no pathogenic or likely pathogenic combination rule in the POLE framework or generic ACMG/AMP 2015, and no benign or likely benign rule (BA1, >=2 strong benign, >=2 supporting benign) is met, 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.2792T>C is a missense substitution (p.Phe931Ser) with SpliceAI max delta 0.008, not a null variant, so PVS1 cannot be triggered.
pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context spliceai final_classification_framework PMID:25741868
PS1 Not met Not met: no established pathogenic allele produces p.Phe931Ser, and the only codon-931 ClinVar record (240446) is uncertain significance, not pathogenic.
clinvar vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PS2 Not assessed Not assessed: no proband or parental testing exists, so the confirmed de novo occurrence PS2 requires cannot be evaluated.
PMID:25741868 vcep_path_250_323
PS3 Not assessed Not assessed: no functional or proofreading assay of POLE p.Phe931Ser was identified, leaving PS3's damaging-effect requirement unevaluable.
final_classification_framework generic_acmg_combination_rules oncokb PMID:25741868 vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PS4 Not met Not met: F931S is absent from Supplementary Table S1 (combined endometrial-cancer count 0, not >=10), so the POLE custom PS4 recurrence rule cannot fire.
vcep_path_250_323_s002 vcep_path_250_323 PMID:28873162 PMID:25394175
PM1 Not met Not met: p.F931S lies outside the POLE exonuclease domain (residues 268-471), where the governing framework restricts PM1 to 14 named hotspot/domain substitutions.
final_classification_framework vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323_s001 pvs1_gene_context clinvar
PM2 Met Met, supporting: gnomAD v4.1 all-comers AF 1.67e-05 is below the 0.0001 PM2 threshold, though Ashkenazi Jewish AF reaches 0.000777.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework PMID:25741868
PM3 Not assessed Not assessed: no trans-partner or phase data exists for heterozygous POLE c.2792T>C, so the recessive in-trans requirement cannot be evaluated.
clinvar vcep_path_250_323 PMID:25741868
PM4 N/A Not applicable: the c.2792T>C substitution changes one residue (p.Phe931Ser) with no protein length change, and SpliceAI max delta 0.008 excludes in-frame splice effects.
pvs1_variant_assessment spliceai final_classification_framework clinvar PMID:25741868
PM5 Not met Not met: zero codon-931 pathogenic or likely pathogenic comparators exist in ClinVar or the VCEP recurrence/in-silico tables.
pm5_candidates clinvar vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
PM6 Not assessed Not assessed: no proband or parental information is reported, so an assumed de novo occurrence cannot be recorded.
PMID:25741868 vcep_path_250_323
PP1 Not assessed Not assessed: no pedigree, affected relatives, or countable meioses are reported, so co-segregation cannot be scored.
PMID:25741868 vcep_path_250_323
PP2 Not assessed Not assessed: no POLE-specific PP2 rule and no gene-level missense-constraint data were available to test the criterion.
PMID:25741868 final_classification_framework vcep_path_250_323
PP3 Met Met at supporting: REVEL 0.749 sits in the PP3-supporting band (>=0.644) and below the 0.773 moderate cutoff.
revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323_s002 vcep_path_250_323 PMID:25741868
PP4 Not assessed Not assessed: no proband phenotype or family history was captured for this case, so phenotype specificity for POLE cannot be evaluated.
clinvar
PP5 Not met Not met: ClinVar VCV000240446 has zero expert-panel submissions (1-star, conflicting; 3 uncertain, 1 likely benign), so no expert-panel pathogenic assertion supports PP5.
clinvar
BA1 Not met Not met: the highest gnomAD subpopulation frequency is 0.00096432 (Ashkenazi Jewish, v2.1), far below the 0.05 BA1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework PMID:25741868
BS1 Not met Not met: the highest gnomAD subpopulation frequency is 0.001014 (Ashkenazi Jewish, v2.1 non-cancer), below the 0.01 BS1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules final_classification_framework PMID:25741868
BS2 Not met Not met: gnomAD reports 0 homozygotes in v2.1, v4.1 and both non-cancer subsets, and the heterozygous carriers are unphenotyped.
gnomad_v2 gnomad_v4 final_classification_framework PMID:25741868
BS3 Not assessed Not assessed: no functional data exist for p.Phe931Ser, and OncoKB records unknown oncogenic effect with no variant-specific evidence.
final_classification_framework generic_acmg_combination_rules oncokb PMID:25741868 vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s003 vcep_path_250_323_s004
BS4 Not assessed Not assessed: no family members with or without the variant are reported, so non-segregation cannot be evaluated.
PMID:25741868 vcep_path_250_323
BP1 Not met Not met: POLE disease is driven by exonuclease-domain missense substitutions, not by truncating variants, so the premise of BP1 does not hold.
PMID:25741868 vcep_path_250_323 final_classification_framework pvs1_gene_context
BP2 Not assessed Not assessed: no cis/trans phase data exist linking c.2792T>C to any pathogenic POLE variant, so BP2 cannot be evaluated.
clinvar vcep_path_250_323 PMID:25741868
BP3 N/A Not applicable: c.2792T>C is a single-base substitution (p.Phe931Ser), not an in-frame indel in a repeat region, and SpliceAI max delta 0.008 excludes cryptic indels.
pvs1_variant_assessment spliceai final_classification_framework clinvar PMID:25741868
BP4 Not met Not met: REVEL 0.749 is far above all BP4 thresholds (supporting cutoff <=0.29), so the missense computational evidence does not indicate a benign effect.
revel bayesdel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 vcep_path_250_323_s002 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 VCV000240446 has no expert-panel submission (1-star, conflicting; 3 uncertain, 1 likely benign), so no expert-panel benign assertion supports BP6.
clinvar
BP7 N/A Not applicable: c.2792T>C is a missense change (p.Phe931Ser), and BP7 applies only to synonymous variants.
PMID:25741868
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