Variant classification summary

NM_006231.4:c.1100T>G

POLE · NP_006222.2:p.(Phe367Cys) · NM_006231.4

GRCh37: chr12:133252327 A>C · GRCh38: chr12:132675741 A>C

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM5 moderate PM2 supporting PP3 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Phe367Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM5 moderate: p.F367S is a pathogenic different missense change at the same residue.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

PP3 supporting: the exact F367C row is REVEL likely disease causing with zero benign predictions.

Final determination: Under the local POLE framework's ACMG/AMP combination rules, one Moderate plus two Supporting pathogenic criteria does not reach Likely Pathogenic or Pathogenic, and no benign rule is met, resulting in VUS.

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.1100T>G is a missense variant (p.Phe367Cys), not one of the specified PVS1 null-variant classes.	pvs1_variant_assessment
PS1	Not assessed	Not assessed: no previously established pathogenic Phe367Cys variant caused by a different nucleotide change was documented in the reviewed sources.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history status, or confirmed maternity and paternity testing is available.
PS3	Not assessed	Not assessed: no validated functional assay result was identified; OncoKB's likely-loss-of-function label is not a documented assay outcome.	oncokb
PS4	Not met	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.	vcep_path_250_323_s002 vcep_path_250_323
PM1	Not met	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.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at Supporting: the variant is absent in gnomAD v2.1 and v4.1, meeting the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive inheritance or parental/offspring phase data show this variant in trans with a pathogenic variant.
PM4	N/A	Not applicable: p.Phe367Cys is a missense substitution with no in-frame indel or stop-loss protein-length change.	pvs1_variant_assessment
PM5	Met	Met at moderate strength: p.F367S is a different missense change at residue 367 and was considered pathogenic in the TCGA-based analysis.	vcep_path_250_323 vcep_path_250_323_s002
PM6	Not assessed	Not assessed: no affected proband or parental-origin evidence supports an assumed de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected family members or segregation results are documented for evaluating co-segregation with disease.
PP2	Not assessed	Not assessed: the reviewed sources provide no validated benign-missense-rate and common-missense-mechanism evidence for POLE.
PP3	Met	Met at supporting: Supplementary Table S3 lists F367C as likely disease causing by REVEL with 0 benign in silico results.	vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no patient phenotype or family-history information is available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification for c.1100T>G.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the BA1 allele-frequency threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele, versus the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult carrier or homozygote observation is available for the BS2 zygosity and penetrance requirement.	gnomad_v2 gnomad_v4
BS3	Not assessed	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.	oncokb
BS4	Not assessed	Not assessed: no affected relatives and no family genotypes are documented to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the reviewed sources do not establish that POLE disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no phase data identify this variant in trans or cis with a pathogenic variant, and inheritance and penetrance are unestablished.
BP3	N/A	Not applicable: c.1100T>G is a missense substitution, not an in-frame deletion or insertion in a repetitive region.	pvs1_variant_assessment
BP4	Not met	Not met: Supplementary Table S3 reports REVEL likely disease causing and 0 benign results, versus the BP4 requirement of Likely benign and >=4.	vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no alternate molecular basis for the patient's disease is documented in the available case evidence.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for c.1100T>G.	clinvar
BP7	N/A	Not applicable: c.1100T>G is missense, producing p.Phe367Cys, not a synonymous substitution required for BP7.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.