Classification rationale

PM2PM5PP3 VUS

POLE c.1100T>G missense · exon 11

PM5 moderate: p.F367S is a pathogenic different missense change at the same residue. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1. PP3 supporting: the exact F367C row is REVEL likely disease causing with zero benign predictions.

PM2 + PM5 + PP3 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_006231.4 · variants mapped to exon structure

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at Supporting: the variant is absent in gnomAD v2.1 and v4.1, meeting the PM2 threshold of <=0.0001.

gnomAD v2.1 all-comers: the variant was absent, corresponding to an observed allele frequency of 0.gnomAD v4.1 all-comers: the variant was absent, corresponding to an observed allele frequency of 0.The supplied generic PM2 calibration is <=0.0001 and specifies PM2 at Supporting strength under the ClinGen SVI recommendation (PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗

PM5 moderate review Pathogenic

Met at moderate strength: p.F367S is a different missense change at residue 367 and was considered pathogenic in the TCGA-based analysis.

PATH-250-323.pdf, abstract: the six additional POLE mutations in the POLE-score >=4 group were considered pathogenic.PATH-250-323.pdf, results text: the six recurrent non-hotspot variants considered pathogenic include F367S.PATH-250-323-s002.xlsx, row p.F367(S^C): COSMIC 2, TCGA 2, total 4; this confirms a different missense substitution at the same residue 367.

PP3 supporting Pathogenic

Met at supporting: Supplementary Table S3 lists F367C as likely disease causing by REVEL with 0 benign in silico results.

León-Castillo et al. 2020 Supplementary Table S3, row F367C: SIFT=Deleterious; PANTHER=probably damaging; SNAP2=Effect; PolyPhen2=probably damaging; PROVEAN=Deleterious; REVEL=likely disease causing; Number of benign results=0.The exact variant was searched as c.1100T>G, p.Phe367Cys, and p.F367C; the governing in-silico table match is the F367C row.The PP3 rule requires an exact missense-table match, REVEL likely disease causing, and <=1 benign result; this row meets all three conditions.

Assessed · not applied · 7 not met · 14 not assessed

Pathogenic

PS1 Not assessed: no previously established pathogenic Phe367Cys variant caused by a different nucleotide change was documented in the reviewed sources.

PS2 Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity testing is available.

PS3 Not assessed: no validated functional assay result was identified; OncoKB's likely-loss-of-function label is not a documented assay outcome.

PS4 Not met: Supplementary Table S1 reports p.F367C in 1 COSMIC case, 0 TCGA cases, and 1 total, below the >=10 and dual-cohort recurrence requirements.

PM1 Not met: p.F367C is absent from the framework's exact PM1 lists, despite one COSMIC occurrence and zero TCGA occurrences in Supplementary Table S1.

PM3 Not assessed: no recessive inheritance or parental/offspring phase data show this variant in trans with a pathogenic variant.

PM6 Not assessed: no affected proband or parental-origin evidence supports an assumed de novo occurrence without confirmed maternity and paternity.

PP1 Not assessed: no affected family members or segregation results are documented for evaluating co-segregation with disease.

PP2 Not assessed: the reviewed sources provide no validated benign-missense-rate and common-missense-mechanism evidence for POLE.

PP4 Not assessed: no patient phenotype or family-history information is available to evaluate specificity for a single-gene disease.

PP5 Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification for c.1100T>G.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the BA1 allele-frequency threshold of >=0.05.

BS1 Not met: gnomAD v2.1 and v4.1 show no observed allele, versus the generic BS1 threshold of >=0.01.

BS2 Not assessed: no healthy-adult carrier or homozygote observation is available for the BS2 zygosity and penetrance requirement.

BS3 Not assessed: no validated functional result showed absence of damage to POLE protein function or splicing; the available record instead reports likely loss of function.

BS4 Not assessed: no affected relatives and no family genotypes are documented to demonstrate lack of segregation.

BP1 Not assessed: the reviewed sources do not establish that POLE disease is caused primarily by truncating variants.

BP2 Not assessed: no phase data identify this variant in trans or cis with a pathogenic variant, and inheritance and penetrance are unestablished.

BP4 Not met: Supplementary Table S3 reports REVEL likely disease causing and 0 benign results, versus the BP4 requirement of Likely benign and >=4.

BP5 Not assessed: no alternate molecular basis for the patient's disease is documented in the available case evidence.

BP6 Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for c.1100T>G.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.775. BayesDel score = 0.197644.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57677432, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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