Variant classification summary

NM_006231.4:c.1662C>A

POLE · NP_006222.2:p.(Ser554Arg) · NM_006231.4

GRCh37: chr12:133249237 G>T · GRCh38: chr12:132672651 G>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ser554Arg)

gnomAD AF

3.0979817268645824e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 Supporting reflects the variant's very low gnomAD frequency, with AF 3.09798e-06 below the 0.0001 threshold.

Final determination: Under the local POLE framework's ACMG/AMP combination rules, one Supporting criterion alone satisfies no pathogenic or benign rule, 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: the variant is a missense substitution, whereas PVS1 names only null variant classes such as nonsense, frameshift, canonical splice, initiation-codon, or exon-deletion variants.	pvs1_variant_assessment
PS1	Not assessed	Not assessed: no established pathogenic variant with the same p.Ser554Arg amino-acid change was identified in the reviewed evidence.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PS2	Not assessed	Not assessed: no parental genotypes or confirmed maternity and paternity are documented to establish a de novo variant in an affected proband.
PS3	Not assessed	Not assessed: no variant-specific functional assay or validated laboratory study was identified for POLE p.Ser554Arg.	oncokb PMID:25394175
PS4	Not met	Not met: c.1662C>A is absent from the governing recurrence tables and is not among the framework's four qualifying hotspot variants.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001 PMID:25394175
PM1	Not met	Not met: p.Ser554Arg is absent from all exact POLE PM1 hotspot, pathogenic-tier, and uncertain-tier substitutions specified by the governing framework.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at supporting: all-comers gnomAD v4.1 AF is 3.09798e-06, below the 0.0001 PM2 threshold, with five alleles and no homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring testing establishes this variant in trans with a pathogenic variant.
PM4	N/A	Not applicable: p.(Ser554Arg) is a missense substitution with no in-frame insertion, deletion, or stop-loss protein-length change.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no pathogenic alternate missense substitution at POLE residue Ser554 was identified in the reviewed evidence.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM6	Not assessed	Not assessed: no de novo occurrence is reported, with or without parental testing, so PM6 cannot be distinguished from absent family data.
PP1	Not assessed	Not assessed: zero affected relatives or informative meioses are documented, so co-segregation with disease cannot be evaluated.
PP2	Not assessed	Not assessed: no gene-wide evidence simultaneously establishes low benign missense variation and a common missense disease mechanism for POLE.	vcep_path_250_323 vcep_path_250_323_s002
PP3	Not met	Not met: REVEL 0.393 is within the generic missense gray zone of 0.250–0.750, and the variant is absent from POLE Tables S2 and S3.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel
PP4	Not assessed	Not assessed: no patient phenotype or family history was available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has two laboratory Uncertain-significance submissions and zero expert-panel submissions for the exact variant.	clinvar PMID:25394175
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.9e-07, far below the 0.05 BA1 threshold, with 62,484 observed alleles in the highest-frequency population.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.9e-07 versus the generic BS1 threshold of 0.01, so the allele is not excessively frequent for the disorder.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no individual healthy-adult phenotype, age, inheritance-state, or penetrance evidence for BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific functional assay or validated laboratory study was identified to demonstrate preserved POLE function or splicing.	oncokb PMID:25394175
BS4	Not assessed	Not assessed: no affected family members were genotyped, so lack of segregation and the phenocopy caveat cannot be evaluated.
BP1	Not assessed	Not assessed: the reviewed evidence does not establish that POLE disease is caused primarily by truncating rather than missense variants.	vcep_path_250_323 vcep_path_250_323_s002
BP2	Not assessed	Not assessed: no family or haplotype data establish this variant in trans or cis with a pathogenic variant.
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame deletion or insertion in a repetitive region without known function.	pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.393 is within the generic missense gray zone of 0.250–0.750, and the variant is absent from POLE Tables S2 and S3.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel
BP5	Not assessed	Not assessed: no clinically characterized case with an alternate molecular basis was documented for this variant.
BP6	Not met	Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification and is recorded as Uncertain significance.	clinvar PMID:25394175
BP7	N/A	Not applicable: c.1662C>A is a missense variant producing p.Ser554Arg, not a synonymous variant required for BP7.

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