Variant classification summary

NM_006231.4:c.6380G>A

POLE · NP_006222.2:p.(Arg2127Gln) · NM_006231.4

GRCh37: chr12:133202854 C>T · GRCh38: chr12:132626268 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg2127Gln)

gnomAD AF

4.337389412060669e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

None of PS2, PM6, PP1, or BS4 can be assessed because the available materials contain no case-level proband, parental, pedigree, affected-relative, meiosis, or segregation data.

2

PS4 is not met under the local POLE framework because the exact variant is absent from the governing recurrence sources and is not in the framework's eligible pathogenic set.

3

PP4 and BP5 are not assessed because the supplied case evidence lacks the required phenotype/family-history or alternate-molecular-basis information.

4

PP5 and BP6 are not met because the exact ClinVar record contains only Uncertain significance clinical-laboratory submissions and no expert-panel classification.

5

Population evidence does not support BA1, BS1, or PM2 under the supplied generic thresholds.

6

BS2 remains not assessed because aggregate population counts do not document a healthy adult carrier or establish the required inheritance, penetrance, and age-of-onset context.

Final determination: Under the local POLE framework's ACMG/AMP combination rules, a VUS results when no pathogenic or benign rule is satisfied and the evidence is not conflicting.

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.6380G>A is a missense substitution, p.Arg2127Gln, rather than a null variant type specified for PVS1.	pvs1_variant_assessment
PS1	Not met	Not met: no previously established pathogenic variant producing the same p.Arg2127Gln amino-acid change was identified.	clinvar vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PS2	Not assessed	Not assessed: no proband-level parental testing, disease phenotype, family-history, or confirmed maternity and paternity are documented.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or reproducible clinical-laboratory evidence was identified for p.Arg2127Gln.	oncokb
PS4	Not met	Not met: p.Arg2127Gln is absent from the governing recurrence table and lacks the required COSMIC-plus-TCGA count >=10 and established hotspot designation.	vcep_path_250_323 vcep_path_250_323_s002
PM1	Not met	Not met: p.Arg2127Gln is absent from the framework's complete exact-variant PM1 lists, including all five hotspots and recurrent exonuclease-domain substitutions.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Not met	Not met: the variant is present in controls, with 1KG:CHB AF 0.00490196 exceeding the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive disease context, affected-proband observation, pathogenic allele, or parental/offspring phase testing is documented.
PM4	N/A	Not applicable: p.Arg2127Gln is a missense substitution with no protein length change from an in-frame indel or stop-loss event.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no defensible pathogenic alternate missense substitution at POLE Arg2127 was available for comparison.	clinvar vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM6	Not assessed	Not assessed: no affected proband, family-history, parental-testing, or unconfirmed-parentage evidence supports an assumed de novo occurrence.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, variant observations, or phenotype-consistent co-segregation data are documented.
PP2	Not assessed	Not assessed: no validated gene-level evidence establishes both a low benign missense rate and a common missense disease mechanism for POLE.
PP3	Not met	Not met: REVEL was 0.313, within the generic missense gray zone of 0.250–0.750 and below the PP3 threshold of >0.750.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or family history sufficiently specific for a single-etiology disease was available for comparison.	generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar reports p.Arg2127Gln as Uncertain significance, with zero expert-panel submissions and no exact pathogenic classification.	clinvar
BA1	Not met	Not met: the highest reported ancestry-specific AF is 0.00490196, below the BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the maximum reported AF is 0.00490196, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: zero homozygotes are reported, but no documented healthy adult carrier or penetrance and age-of-onset assessment is available.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay demonstrated preserved protein function or normal splicing for p.Arg2127Gln.	oncokb
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant, phenotype review, or informative non-segregation data are available.
BP1	Not assessed	Not assessed: no validated gene-level evidence shows that POLE disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no qualifying dominant inheritance context or documented cis/trans observation with a pathogenic variant is available.
BP3	N/A	Not applicable: p.Arg2127Gln is a missense substitution, not an in-frame deletion or insertion eligible for BP3.	pvs1_variant_assessment
BP4	Not met	Not met: REVEL was 0.313, above the generic missense BP4 threshold of <0.250 and within the 0.250–0.750 gray zone.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular basis for disease was documented in the available case evidence.	generic_acmg_combination_rules
BP6	Not met	Not met: ClinVar reports p.Arg2127Gln as Uncertain significance, with zero expert-panel submissions and no exact benign classification.	clinvar
BP7	N/A	Not applicable: c.6380G>A changes p.Arg2127 to p.Gln and is not a synonymous variant required for BP7.

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