LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_006231.4_c.857C_G_20261029_031529
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.857C>G

POLE  · NP_006222.2:p.(Pro286Arg)  · NM_006231.4
GRCh37: chr12:133253184 G>C  ·  GRCh38: chr12:132676598 G>C
Gene: POLE Transcript: NM_006231.4
Final call
Pathogenic
PS1 strong PM1 strong PS3 supporting PS4 supporting 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.(Pro286Arg)
gnomAD AF
ClinVar
drug response
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 Strong establishes the identical p.Pro286Arg amino-acid change as pathogenic.
2
Pathogenic: PM1 Strong identifies p.P286R as an established POLE exonuclease-domain hotspot.
3
Supporting: PS3 shows reduced human POLE exonuclease activity and a strong mutator phenotype in the corresponding yeast allele.
4
Supporting: PS4 documents 181 exact p.P286R endometrial carcinoma observations across COSMIC and TCGA.
5
Supporting: PM2 shows absence from gnomAD v2.1 and v4.1.
6
Supporting: PP3 reports likely disease-causing REVEL classification with zero benign in-silico results.
Final determination: Under the local POLE framework's ACMG/AMP thresholds, two Strong pathogenic criteria (PS1 Strong and PM1 Strong) satisfy the Pathogenic rule.
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.857C>G is a missense p.Pro286Arg substitution, not one of the generic PVS1 null-variant types.
pvs1_variant_assessment pvs1_generic_framework
PS1 Met Met: p.P286R is one of five POLE mutations with confirmed pathogenicity, and SpliceAI max delta is only 0.002.
vcep_path_250_323 PMID:25224212 PMID:24525744 spliceai
PS2 Not assessed Not assessed: no documented proband-parent testing, maternity/paternity confirmation, or family-history data establish a de novo germline event.
PMID:23263490 PMID:24525744
PS3 Met Met at Supporting: exact P286R reduced human POLE exonuclease activity and the corresponding yeast allele increased mutation rates up to 370-fold versus wild type.
PMID:25228659 PMID:24525744
PS4 Met Met at Supporting: p.P286R occurred in 160 COSMIC and 21 TCGA endometrial carcinomas, totaling 181 cases and satisfying the framework's >=10 recurrence requirement.
vcep_path_250_323 vcep_path_250_323_s002 PMID:23447401 PMID:23636398 PMID:25224212
PM1 Met Met at Strong: the governing POLE framework explicitly assigns PM1_Strong to exact hotspot p.P286R.
vcep_path_250_323 vcep_path_250_323_s002
PM2 Met Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no second pathogenic allele or parental/offspring phase testing establishes NM_006231.4:c.857C>G in trans in an affected proband.
PM4 N/A Not applicable: c.857C>G causes the missense change p.Pro286Arg, with no in-frame indel, stop-loss, or protein-length change.
pvs1_variant_assessment
PM5 Not met Not met: no different Pro286 missense substitution is established as pathogenic in the searched governing POLE materials.
vcep_path_250_323 vcep_path_250_323_s002
PM6 Not assessed Not assessed: no germline de novo occurrence in an affected patient is documented, even without parental confirmation.
PMID:23263490 PMID:24525744
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or germline co-segregation results are documented for P286R.
PMID:23263490 PMID:24525744
PP2 Not assessed Not assessed: the available sources lack the required gene-level benign missense rate and generic PP2 mechanism evidence.
PP3 Met Met (supporting): P286R has REVEL class ‘likely disease causing’ and 0 benign in-silico results, satisfying the POLE PP3 rule.
vcep_path_250_323_s003
PP4 Not assessed Not assessed: no patient phenotype or family history is available to determine whether it is highly specific for a single-gene disease.
PP5 Not met Not met: ClinVar has zero expert-panel submissions, so its single-submitter Likely pathogenic assertion cannot trigger PP5.
clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the >=5% allele frequency required for BA1.
gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, so the variant does not exceed the generic 1% BS1 default.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: population databases report absence but provide no healthy adult genotype or phenotype observation needed to evaluate BS2.
gnomad_v2 gnomad_v4
BS3 Not met Not met: exact human P286R reduced 3′–5′ exonuclease activity, while corresponding yeast assays increased mutation rates up to 370-fold versus wild type.
PMID:25228659 PMID:24525744
BS4 Not assessed Not assessed: no affected relatives with negative variant testing or pedigree-level non-segregation data are documented.
PMID:23263490 PMID:24525744
BP1 Not met Not met: POLE pathogenicity is documented for recurrent exonuclease-domain missense hotspots, including p.P286R, not primarily truncating variants.
vcep_path_250_323 vcep_path_250_323_s002 PMID:23263490
BP2 Not assessed Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic variant under the BP2 inheritance conditions.
BP3 N/A Not applicable: p.Pro286Arg is a missense substitution, not an in-frame deletion or insertion in a repetitive region without known function.
pvs1_variant_assessment
BP4 Not met Not met: P286R is ‘likely disease causing’ with 0 benign results, whereas the POLE BP4 rule requires a benign REVEL class and at least 4 benign results.
vcep_path_250_323_s003 spliceai
BP5 Not assessed Not assessed: no patient-level alternate molecular basis for disease is documented alongside this variant.
BP6 Not met Not met: ClinVar has zero expert-panel submissions and no qualifying expert-panel Benign or Likely benign classification.
clinvar
BP7 N/A Not applicable: c.857C>G is a missense variant producing p.Pro286Arg, not a synonymous variant.
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