Variant classification summary

NM_006231.4:c.4519_4520del

POLE · NP_006222.2:p.(Gln1507AlafsTer37) · NM_006231.4

GRCh37: chr12:133219840 CTG>C · GRCh38: chr12:132643254 CTG>C

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.(Gln1507AlafsTer37)

gnomAD AF

6.196308982665206e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): 2-bp frameshift (p.Gln1507AlafsTer37) in exon 35 of 49 predicted to trigger nonsense-mediated decay, removing essential C-terminal domains.

2

PM2 (Moderate): highest observed allele frequency 0.000176%, far below the <0.1% rarity threshold.

3

PVS1 (Very Strong) plus PM2 (Moderate) under standard ACMG/AMP 2015 combination rules supports Likely Pathogenic.

Final determination: 1 Very Strong (PVS1) + 1 Moderate (PM2) with no other criteria met satisfies the framework's 'PVS1_VeryStrong + 1 Moderate' 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): 2-bp frameshift (p.Gln1507AlafsTer37) in exon 35 of 49 predicted to trigger nonsense-mediated decay.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:30503519 PMID:23230001
PS1	N/A	Not applicable: PS1 applies only to missense variants, and this is a frameshift deletion.
PS2	Not assessed	Not assessed: no documented de novo occurrence or parental testing was available for this variant.
PS3	Not assessed	Not assessed: no functional assay evidence for this variant was available.
PS4	Not met	Not met: this frameshift is outside the defined POLE somatic hotspot set and has no COSMIC record.	final_classification_framework oncokb
PM1	N/A	Not applicable: PM1 covers exonuclease-domain missense hotspots; this frameshift lies outside that domain at residue 1507.	vcep_path_250_323
PM2	Met	Met (Moderate): highest observed allele frequency 0.000176%, far below the <0.1% rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no observation of this variant with a second pathogenic POLE variant, or phase/segregation data, was available.
PM4	N/A	Not applicable: PM4 applies to in-frame indels; this 2-bp deletion shifts the reading frame.	pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires an established pathogenic missense at the same residue; this is a frameshift.	pm5_candidates
PM6	Not assessed	Not assessed: no reported de novo occurrence, even without confirmed parentage, was available.
PP1	Not assessed	Not assessed: no family segregation data was reported for this variant.
PP2	N/A	Not applicable: PP2 is missense-specific, and this variant is a truncating frameshift.
PP3	N/A	Not applicable: in-silico tools are not computed for frameshifts; SpliceAI max delta 0.014 shows no splice impact.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or diagnosis data was supplied to evaluate phenotypic specificity.
PP5	Not met	Not met: ClinVar contains no expert-panel pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: highest allele frequency 0.000176%, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: highest allele frequency 0.000176%, far below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: zero homozygotes in gnomAD v4.1 and no unaffected-carrier observations.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence of normal activity was available.
BS4	Not assessed	Not assessed: no affected non-carriers or unaffected carriers were reported to test segregation.
BP1	N/A	Not applicable: BP1 evaluates missense variants in truncating-only disease genes; this variant is itself truncating.
BP2	Not assessed	Not assessed: no data on this variant in cis with another pathogenic POLE variant was available.
BP3	N/A	Not applicable: BP3 covers in-frame indels in repetitive regions; this is an out-of-frame deletion.	pvs1_variant_assessment
BP4	N/A	Not applicable: REVEL/BayesDel are not computed for frameshifts, and SpliceAI max delta 0.014 shows no splice disruption.	spliceai
BP5	Not assessed	Not assessed: no evidence of an alternative cause for the presenting condition was supplied.
BP6	Not met	Not met: ClinVar contains no expert-panel benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this is a 2-bp frameshift deletion.

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