Variant classification summary

NM_006231.4:c.4307G>A

POLE · NP_006222.2:p.(Arg1436Gln) · NM_006231.4

GRCh37: chr12:133220130 C>T · GRCh38: chr12:132643544 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg1436Gln)

gnomAD AF

3.345749782526264e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

For p.Arg1436Gln (NM_006231.4:c.4307G>A), the governing POLE material records one somatic COSMIC occurrence but does not place the variant among the exact pathogenic hotspot or non-hotspot PM1 substitutions.

2

The variant is not supported by PS1, PM1, PM5, PP2, or BP1 on the reviewed evidence; PM5, PP2, and BP1 remain not assessed where the required validated comparator or gene-level calibration is unavailable.

3

No segregation or de novo criterion is met from the available evidence.

4

A ClinVar submission signal mentioning an unaffected brother is insufficiently documented to establish BS4.

Final determination: Under the local POLE framework's ACMG/AMP 2015 combination rules, all other combinations, including absence of qualifying pathogenic or benign evidence, result 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.4307G>A is a missense substitution, p.(Arg1436Gln), rather than a nonsense, frameshift, or canonical splice loss-of-function variant.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	Not met: no established pathogenic POLE variant producing the same Arg1436Gln amino-acid change was identified.	vcep_path_250_323 vcep_path_250_323_s002 final_classification_framework
PS2	Not assessed	Not assessed: no documented proband-parent testing or confirmed de novo observation is available for the POLE c4307G>A variant.	PMID:25741868
PS3	Not assessed	Not assessed: no validated variant-specific functional assay is available, and computational predictions were explicitly unconfirmed by functional testing.	clinvar PMID:25741868
PS4	Not met	Not met: the exact variant appears once overall in Table S1 (COSMIC 1, TCGA 0), below the governing recurrence definition of at least two combined cases.	vcep_path_250_323_s002 vcep_path_250_323
PM1	Not met	Not met: p.R1436Q is absent from POLE's exact PM1 variant lists and is not identified as an approved critical-domain variant.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001 final_classification_framework
PM2	Not met	Not met: gnomAD v4.1 group-maximum frequency is 0.00012744, exceeding the PM2 threshold of 0.0001 despite an overall frequency of 3.34575e-05.	gnomad_v4
PM3	N/A	Not applicable: POLE germline disease context is heterozygous, with no applicable recessive disorder or affected-proband variant-in-trans observation documented.	PMID:25741868
PM4	N/A	Not applicable: c.4307G>A causes the single-residue substitution p.(Arg1436Gln) and produces no documented protein-length change.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no established pathogenic alternate substitution at POLE residue 1436 was available for comparison.	pm5_candidates vcep_path_250_323_s002 vcep_path_250_323 vcep_path_250_323_s001
PM6	Not assessed	Not assessed: no affected-proband report or presumed de novo observation is documented for the POLE c4307G>A variant.	PMID:25741868
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, pedigree, or segregation results are documented for the POLE c4307G>A variant.	PMID:25741868
PP2	Not assessed	Not assessed: no validated POLE-specific evidence establishes the missense-mechanism pattern required for PP2.	final_classification_framework vcep_path_250_323
PP3	Not met	Not met: REVEL 0.42 is below the generic PP3 threshold of 0.644, and POLE Table S3 classifies R1436Q as Likely-benign.	revel vcep_path_250_323_s004
PP4	Not assessed	Not assessed: no case-specific, highly specific POLE phenotype is documented for comparison with the variant's associated disorders.	clinvar oncokb
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant and no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 highest population frequency is 0.000216652, far below the BA1 threshold of 0.05.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 highest population frequency is 0.000216652, below the BS1 threshold of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 reports zero homozygotes, but provides no phenotype-confirmed healthy-carrier evidence for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated variant-specific functional assay demonstrates a normal effect, and no benign assay threshold or control data are available.	clinvar PMID:25741868
BS4	Not assessed	Not assessed: a ClinVar signal mentions an unaffected brother, but lacks verifiable family genotypes, phenotype assessment, and segregation methodology.	clinvar PMID:25741868
BP1	Not assessed	Not assessed: no validated POLE-specific evidence shows that disease is caused mainly by non-missense variants.	final_classification_framework vcep_path_250_323
BP2	Not assessed	Not assessed: no affected-proband co-occurrence, second pathogenic variant, or cis/trans phase result is documented for this variant.	PMID:25741868
BP3	N/A	Not applicable: p.(Arg1436Gln) is a missense substitution, not an in-frame insertion or deletion in a repetitive protein region.	pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.42 exceeds the generic BP4 threshold of 0.29, and POLE Table S3 reports only one benign in-silico result.	revel vcep_path_250_323_s004
BP5	Not assessed	Not assessed: no validated alternative molecular diagnosis or co-occurrence evidence is documented to explain the relevant phenotype.	clinvar
BP6	Not met	Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification, despite one ordinary Likely benign submission.	clinvar
BP7	N/A	Not applicable: c.4307G>A changes Arg1436 to Gln and is missense, whereas BP7 applies only to synonymous variants.

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