Variant classification summary

NM_006231.4:c.2964G>T

POLE · NP_006222.2:p.(Ser988=) · NM_006231.4

GRCh37: chr12:133237651 C>A · GRCh38: chr12:132661065 C>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ser988=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — no carriers in large control populations.

2

BP7 (Supporting): synonymous p.Ser988= with SpliceAI max delta 0.01, predicting no splice impact.

3

Overall: VUS — the conflicting PM2 and BP7 supporting evidence satisfies no enumerated Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination.

Final determination: The only met criteria are PM2 (supporting, pathogenic direction) and BP7 (supporting, benign direction), which conflict, and no enumerated ACMG/AMP 2015 Pathogenic/Likely Pathogenic/Benign/Likely Benign combination is satisfied, so the framework combination rule classifies this as Uncertain Significance (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: c.2964G>T is synonymous (p.Ser988=) with no predicted splice impact, so it is not a null variant (SpliceAI max delta 0.01).	pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context spliceai generic_acmg_combination_rules final_classification_framework
PS1	N/A	Not applicable: the variant is synonymous (p.Ser988=), so no amino acid change exists to match a known pathogenic change.	pvs1_variant_assessment pm5_candidates vcep_path_250_323 PMID:25394175
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parental testing is documented in ClinVar or the literature.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PS3	Not assessed	Not assessed: no functional assay of this variant exists; the only related data is an in silico SpliceAI prediction (max delta 0.01), not a functional study.	PMID:25394175 vcep_path_250_323 spliceai generic_acmg_combination_rules
PS4	Not met	Not met: the gene-specific rule applies only to recurrent missense variants (none at residue 988), and no case-control study exists for this variant.	final_classification_framework vcep_path_250_323_s002 clinvar PMID:25394175
PM1	N/A	Not applicable: p.Ser988= is synonymous and lies outside the exonuclease domain (residues ~268-471) where all framework hotspots reside.	vcep_path_250_323 vcep_path_250_323_s002 pvs1_variant_assessment PMID:25394175
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the 'absent in controls' population criterion.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband genotype or phase data exist to evaluate a trans configuration with a pathogenic variant.	clinvar pm5_candidates generic_acmg_combination_rules final_classification_framework PMID:25394175
PM4	N/A	Not applicable: a synonymous single-nucleotide substitution changes no amino acid and introduces no in-frame indel.	generic_acmg_combination_rules final_classification_framework
PM5	N/A	Not applicable: the variant is synonymous (p.Ser988=), so there is no missense change to compare against a known pathogenic change.	pm5_candidates pvs1_variant_assessment vcep_path_250_323 PMID:25394175
PM6	Not assessed	Not assessed: no de novo occurrence, with or without parentage confirmation, is documented for this variant.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PP1	Not assessed	Not assessed: no segregation study or family testing data exists — zero informative meioses are documented.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
PP2	N/A	Not applicable: PP2 applies to missense variants, and this variant is synonymous (p.Ser988=).	pvs1_variant_assessment vcep_path_250_323 PMID:25394175
PP3	Not met	Not met: SpliceAI predicts no splice impact (max delta 0.01), the only predictor available, so no computational evidence supports a deleterious effect.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 final_classification_framework generic_acmg_combination_rules pvs1_variant_assessment
PP4	Not assessed	Not assessed: no proband phenotype or family-history data for a carrier of this variant is available.
PP5	Not met	Not met: no ClinVar expert-panel (3-star) pathogenic classification exists; the only submission is a 1-star laboratory 'Likely benign'.	clinvar
BA1	Not met	Not met: the variant is absent (frequency 0) from gnomAD v2.1, v4.1, and gnomAD-Canada, so no population threshold is exceeded.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: observed frequency is 0 in all three population databases, the opposite of a frequency greater than expected.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy adult carriers or homozygotes are observed; the variant is absent from all three population databases.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies of this variant exist; in silico and population data cannot substitute for them.	spliceai clinvar oncokb PMID:25394175 vcep_path_250_323 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no affected family member has been tested and reported as not carrying the variant.	clinvar PMID:25394175 generic_acmg_combination_rules final_classification_framework
BP1	N/A	Not applicable: BP1 applies to missense variants, and this variant is synonymous (p.Ser988=).	pvs1_variant_assessment vcep_path_250_323 pvs1_gene_context PMID:25394175
BP2	Not assessed	Not assessed: no genotype data exists to establish a trans or cis configuration with a pathogenic variant.	clinvar pm5_candidates generic_acmg_combination_rules final_classification_framework PMID:25394175
BP3	N/A	Not applicable: the variant is a single-nucleotide substitution, not an in-frame indel in a repeat region.	generic_acmg_combination_rules final_classification_framework
BP4	Not met	Not met: the only 'no impact' prediction (SpliceAI max delta 0.01) is already counted under BP7; no independent benign computational line exists.	spliceai vcep_path_250_323_s003 vcep_path_250_323_s004 final_classification_framework generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no reported carrier with an alternate molecular basis exists, so an alternate diagnosis can be neither established nor excluded.
BP6	Not met	Not met: the 'Likely benign' label is a 1-star laboratory submission, not an expert-panel classification, so BP6 does not apply.	clinvar
BP7	Met	Met (supporting): synonymous p.Ser988= with SpliceAI max delta 0.01, far below the 0.2 impact threshold, predicting no splice effect.	spliceai pvs1_variant_assessment generic_acmg_combination_rules

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