Variant classification summary

NM_006231.4:c.590G>T

POLE · NP_006222.2:p.(Arg197Met) · NM_006231.4

GRCh37: chr12:133254294 C>A · GRCh38: chr12:132677708 C>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg197Met)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

BP4 (Supporting): REVEL score 0.224 is below the 0.290 benign supporting threshold.

3

With one supporting pathogenic and one supporting benign criterion, no ACMG/AMP 2015 combination is satisfied, yielding a final classification of VUS.

Final determination: Under the local POLE framework's ACMG/AMP 2015 combination rules, one supporting pathogenic criterion plus one supporting benign criterion satisfies no pathogenic, likely pathogenic, benign, or likely benign combination and is therefore 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	Not met	Not met: c.590G>T is a missense substitution (p.Arg197Met), not a null variant such as nonsense, frameshift, or canonical splice.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	Not assessed: no confirmed pathogenic variant producing the same p.Arg197Met change was available for comparison.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parental testing was documented.
PS3	Not assessed	Not assessed: no validated disease-relevant functional assay data for p.Arg197Met were available.	oncokb
PS4	Not met	Not met: p.Arg197Met is not recurrent in COSMIC or TCGA endometrial cohorts, and no case-control enrichment data were available.	final_classification_framework vcep_path_250_323_s002 oncokb
PM1	Not met	Not met: p.Arg197Met is not one of the established exonuclease-domain hotspot or recurrent variants under the local POLE framework.	final_classification_framework vcep_path_250_323
PM2	Met	Met (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no observation of the variant in trans with a pathogenic allele in an affected individual was documented.
PM4	Not met	Not met: single-nucleotide missense with no protein-length change; not an in-frame insertion/deletion or stop-loss variant.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no independently established pathogenic missense variant at residue Arg197 was identified.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no unconfirmed de novo occurrence was documented.
PP1	Not assessed	Not assessed: no pedigree or variant-status data from affected relatives were available for segregation analysis.
PP2	Not assessed	Not assessed: no gene-level evidence that pathogenic POLE missense variation is common while benign missense variation is uncommon.	final_classification_framework
PP3	Not met	Not met: REVEL score 0.224 is below the pathogenic supporting calibration threshold.	final_classification_framework revel
PP4	Not assessed	Not assessed: no proband phenotype or family history was provided to assess phenotype specificity.
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic classification exists to support it.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no allele frequency approaching a stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from all three population resources, so no allele frequency exceeds the disease-expected maximum credible frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no unaffected adult carriers or homozygotes were documented.
BS3	Not assessed	Not assessed: no validated functional assay demonstrating a normal effect of p.Arg197Met was available.	oncokb
BS4	Not assessed	Not assessed: no informative affected or unaffected relatives with documented genotype and phenotype.
BP1	Not assessed	Not assessed: no evidence that POLE disease is predominantly caused by truncating variants while missense is not an established mechanism.	final_classification_framework vcep_path_250_323
BP2	Not assessed	Not assessed: no observation of the variant in trans or cis with a pathogenic allele was available.
BP3	Not met	Not met: p.Arg197Met is a missense substitution, not an in-frame insertion/deletion.	pvs1_variant_assessment
BP4	Met	Met (Supporting): REVEL score 0.224 is below the 0.290 BP4 supporting threshold.	final_classification_framework revel
BP5	Not assessed	Not assessed: no proband phenotype or independent molecular diagnosis was provided to assess an alternate cause.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign classification exists to support it.	clinvar
BP7	N/A	Not applicable: c.590G>T is a missense variant (p.Arg197Met), not a synonymous variant.

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.