NM_006231.4:c.941C>A

POLE · NP_006222.2:p.(Ser314Ter) · NM_006231.4

GRCh37: chr12:133252759 G>T · GRCh38: chr12:132676173 G>T

Gene: POLE Transcript: NM_006231.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ser314Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (Very Strong): nonsense variant p.(Ser314Ter) predicted to trigger nonsense-mediated decay, truncating >85% of the protein including the proofreading domain.

PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets.

Combined, PVS1 (Very Strong) + PM2 (Moderate) yields Likely Pathogenic.

Final determination: PVS1_VeryStrong + 1 Moderate (PM2) satisfies the local POLE framework's likely_pathogenic rule.

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	Met	Met (Very Strong): c.941C>A creates stop codon p.(Ser314Ter), predicted to trigger nonsense-mediated decay and remove >85% of POLE's 2286-aa protein. Flagged for human review: gene-disease mechanism and zygosity for this truncating allele are unconfirmed.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	N/A	Not applicable: PS1 compares missense changes; this variant creates a stop codon, so no amino acid change exists to match a known pathogenic variant.
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.
PS3	Not assessed	Not assessed: no functional assay data (e.g., proofreading activity or splicing assays) for this variant were available.
PS4	N/A	Not applicable: the POLE framework's PS4 rule covers four specific recurrent missense substitutions; c.941C>A is a nonsense variant.	final_classification_framework
PM1	N/A	Not applicable: PM1 hotspot rules cover specific missense substitutions only; this is a truncating change, and applying PM1 would double-count PVS1.
PM2	Met	Met (Moderate): absent from the gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets.	gnomad_v2 gnomad_v4 gnomad_canada final_classification_framework generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband with a pathogenic POLE variant in trans with this variant was reported.
PM4	N/A	Not applicable: PM4 covers in-frame indels or stop-loss variants; this is a premature stop codon already captured by PVS1.	pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change at a codon with a known pathogenic missense; this variant creates a stop codon.
PM6	Not assessed	Not assessed: no parental testing or reported de novo occurrence was available.
PP1	Not assessed	Not assessed: no family segregation data, such as relatives' genotypes or informative meioses, were reported.
PP2	N/A	Not applicable: PP2 applies to missense variants only; this is a nonsense change.
PP3	Not met	Not met: SpliceAI max delta 0.132 falls in the gray zone (0.1-0.2), below the >0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype specific to a POLE-associated condition was documented.
PP5	Not met	Not met: no ClinVar record for this exact variant exists, so no expert-panel pathogenic assertion supports PP5.	clinvar
BA1	Not met	Not met: variant absent from the queried gnomAD datasets, so no allele frequency exists to meet a benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: variant absent from the queried gnomAD datasets, so no frequency exceeds that expected for POLE-associated disease.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no observation of this variant in well-phenotyped unaffected adults was provided.
BS3	Not assessed	Not assessed: no functional assay evidence showing a benign effect for this variant was available.
BS4	Not assessed	Not assessed: no affected relatives lacking this variant or other non-segregation observations were reported.
BP1	N/A	Not applicable: BP1 concerns missense variants in truncating-disease genes; this variant is itself truncating.
BP2	Not assessed	Not assessed: no co-occurrence data place this variant in cis or in trans with a pathogenic variant.
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions; this is a nonsense substitution.	pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI max delta 0.132 is above the <0.1 BP4 threshold.	spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis fully explaining a documented phenotype was provided.
BP6	Not met	Not met: no ClinVar record for this exact variant exists, so no expert-panel benign assertion supports BP6.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this variant creates a stop codon.	pvs1_variant_assessment

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