Variant classification summary

NM_006231.4:c.1347G>A

POLE · NP_006222.2:p.(Thr449=) · NM_006231.4

GRCh37: chr12:133250173 C>T · GRCh38: chr12:132673587 C>T

Gene: POLE Transcript: NM_006231.4

Final call

Likely Benign

BS1 supporting BS2 supporting BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Thr449=)

gnomAD AF

0.0006821104746124682 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Supporting): gnomAD v4.1 Finnish allele frequency 0.3885% (243/62,548) exceeds the 0.3% threshold.

2

BS2 (Supporting): homozygotes in the general population (3 in gnomAD v4.1, 1 in gnomAD v2.1) indicate a benign or low-penetrance allele.

3

BP4 (Supporting): SpliceAI max delta 0.07 is below the 0.1 threshold, indicating no predicted splice impact for this synonymous variant.

4

Likely Benign: three supporting benign criteria (BS1, BS2, BP4) satisfied the local POLE framework's rule of at least two.

Final determination: Under the usable local POLE ACMG/AMP framework, at least two supporting benign criteria result in a Likely Benign classification.

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	Not met	Not met: the variant is synonymous (p.Thr449=), not a null variant, and SpliceAI max delta 0.07 predicts no splice disruption.	pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: PS1 requires a missense change, but this synonymous variant (p.Thr449=) alters no amino acid.	clinvar
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with verified maternity/paternity and negative parental testing was documented.
PS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating a damaging effect was available.	generic_acmg_combination_rules PMID:25741868
PS4	Not met	Not met: this synonymous variant is not a qualifying recurrent missense variant (COSMIC/TCGA, count >=10) for PS4_Supporting.	final_classification_framework vcep_path_250_323_s002
PM1	N/A	Not applicable: PM1 is a missense-domain criterion, and this synonymous variant does not change an amino acid.	clinvar vcep_path_250_323
PM2	Not met	Not met: the variant is common in population databases, e.g. gnomAD v4.1 at 1,100 of 1,612,642 alleles.	gnomad_v4 gnomad_v2 gnomad_canada final_classification_framework
PM3	Not assessed	Not assessed: no affected-proband observation or second pathogenic allele was documented to test for trans configuration.	generic_acmg_combination_rules PMID:25741868
PM4	Not met	Not met: the synonymous change leaves amino-acid sequence and protein length unchanged, unlike PM4's in-frame indel or stop-loss variants.	PMID:25741868 pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with an established pathogenic alteration, but residue 449 is unchanged.	clinvar
PM6	Not assessed	Not assessed: no presumed de novo occurrence was reported for this variant.
PP1	Not assessed	Not assessed: no segregation data from affected relatives were available.
PP2	N/A	Not applicable: PP2 is a gene-level missense criterion, and this variant is synonymous.	clinvar
PP3	Not met	Not met: SpliceAI max delta 0.07 is below the >0.2 threshold for predicted splice impact.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype data confirmed a presentation highly specific to POLE-related disease.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: the top population frequency, 0.3885% in gnomAD v4.1 Finnish individuals, is below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 final_classification_framework
BS1	Met	Met (Supporting): gnomAD v4.1 Finnish allele frequency 0.3885% (243/62,548) exceeds the 0.3% BS1 threshold. Flagged for human review: the high frequency is driven mainly by Finnish-ancestry individuals.	gnomad_v4 gnomad_v2 gnomad_canada final_classification_framework
BS2	Met	Met (Supporting): homozygotes in population cohorts (3 in gnomAD v4.1, 1 in v2.1) indicate a benign or low-penetrance allele. Flagged for human review: gnomAD lacks phenotype-confirmed healthy-adult status.	gnomad_v4 gnomad_v2 gnomad_canada final_classification_framework
BS3	Not assessed	Not assessed: no functional assay evidence of a normal (non-damaging) effect was available.	generic_acmg_combination_rules PMID:25741868 PMID:26467025
BS4	Not assessed	Not assessed: no unaffected relatives tested negative to provide non-segregation evidence.
BP1	N/A	Not applicable: BP1 addresses missense variants, and this change is synonymous.	clinvar
BP2	Not assessed	Not assessed: no phase or inheritance data placed this variant in trans or cis with a pathogenic variant.	generic_acmg_combination_rules PMID:25741868
BP3	Not met	Not met: BP3 concerns in-frame insertions/deletions, and this is a synonymous single-nucleotide change.	PMID:25741868 pvs1_variant_assessment
BP4	Met	Met (Supporting): SpliceAI max delta 0.07 is below the <=0.1 BP4 threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis explaining the clinical presentation was identified.	clinvar
BP6	Not met	Not met: no ClinVar expert-panel benign assertion exists for this exact variant.	clinvar
BP7	Not assessed	Not assessed: splice impact is absent (max delta 0.07), but nucleotide-conservation evidence was unavailable to complete BP7.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.