NM_006231.4:c.2113C>T

POLE · NP_006222.2:p.(Arg705Trp) · NM_006231.4

GRCh37: chr12:133245002 G>A · GRCh38: chr12:132668416 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg705Trp)

gnomAD AF

5.581014628459454e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

VUS: PM2 supporting because the gnomAD v4.1 allele frequency is 5.581014628459454e-06, below 0.0001.

VUS: no pathogenic criterion is met for this missense variant.

VUS: no benign criterion or benign combination is met.

Final determination: Under the local POLE framework's ACMG/AMP 2015 combination thresholds, one supporting PM2 criterion alone matches no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule and therefore yields 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: NM_006231.4:c.2113C>T is a missense variant, p.Arg705Trp, not a nonsense, frameshift, or canonical splice loss-of-function variant.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	Not met: governing tables identify R705W but no different pathogenic Arg705 substitution establishing the same-amino-acid-change criterion.	vcep_path_250_323 vcep_path_250_323_s002
PS2	Not assessed	Not assessed: no proband-parent testing or confirmed de novo observation is documented for NM_006231.4:c.2113C>T.	clinvar
PS3	Not assessed	Not assessed: no variant-specific validated functional assay, controls, or damaging functional readout were documented for p.Arg705Trp.	oncokb PMID:25741868
PS4	Not met	Not met: p.R705W appears in 0 COSMIC and 1 TCGA endometrial-carcinoma case, totaling 1 versus the >=10 PS4 requirement.	vcep_path_250_323_s002 vcep_path_250_323
PM1	Not met	Not met: R705W is exon 19 with EDM Signature 10 contribution N and is absent from the governing POLE PM1 exact-variant lists.	vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 5.581014628459454e-06, below the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband, second-pathogenic-variant, or validated in-trans phase observation is available for PM3.
PM4	N/A	Not applicable: p.Arg705Trp is a missense substitution with no amino-acid insertion, deletion, or protein-length change.	generic_acmg_combination_rules pvs1_variant_assessment
PM5	Not met	Not met: no different pathogenic or likely pathogenic missense variant at Arg705 was identified in the governing tables.	vcep_path_250_323 vcep_path_250_323_s002
PM6	Not assessed	Not assessed: no unconfirmed de novo observation or parental genotyping is documented for this POLE variant.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation results are documented.	clinvar
PP2	Not met	Not met: no applicable POLE PP2 rule or validated low-benign-missense/high-pathogenic-missense dataset supports this exon 19 variant.	vcep_path_250_323
PP3	Not met	Not met: REVEL 0.321 is below the generic PP3 supporting threshold of 0.644 and the POLE table labels p.R705W Likely benign, not likely disease causing.	vcep_path_250_323_s003 revel
PP4	Not assessed	Not assessed: no patient-level phenotype or disease-specific clinical feature set is available to evaluate PP4.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for this exact variant, and the aggregate classification is Uncertain significance.	clinvar
BA1	Not met	Not met: the highest observed population AF is 5.04083e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS1	Not met	Not met: the highest observed population AF is 5.04083e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report 0 homozygotes, with no healthy-adult or penetrance evidence supporting BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay, controls, or normal-function readout were documented for p.Arg705Trp.	oncokb PMID:25741868
BS4	Not assessed	Not assessed: no informative unaffected-relative testing or documented non-segregation is available for this variant.	clinvar
BP1	Not met	Not met: POLE has established pathogenic missense exonuclease-domain variants, so a primarily truncating disease mechanism is not established for BP1.	vcep_path_250_323
BP2	Not assessed	Not assessed: no linked pathogenic variant or phase-resolved cis observation is available to evaluate BP2.
BP3	N/A	Not applicable: p.Arg705Trp is not an in-frame insertion or deletion in a repetitive region and has no repeat-associated protein-length alteration.	generic_acmg_combination_rules pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.321 exceeds the generic BP4 supporting threshold of 0.29, while the POLE table reports only 1 benign result versus the required 4.	vcep_path_250_323_s003 revel
BP5	Not assessed	Not assessed: no affected individual with a documented alternative pathogenic molecular explanation is reported in the available case evidence.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign classification exists; available submissions are all Uncertain significance.	clinvar
BP7	N/A	Not applicable: c.2113C>T is missense and changes p.Arg705 to Trp, whereas BP7 applies only to synonymous variants.

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