Classification rationale

PM2 BP7 VUS

POLE c.2964G>T

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — no carriers in large control populations. BP7 (Supporting): synonymous p.Ser988= with SpliceAI max delta 0.01, predicting no splice impact. Overall: VUS — the conflicting PM2 and BP7 supporting evidence satisfies no enumerated Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination.

PM2 + BP7 → VUS

Gene diagram · NM_006231.4 · variants mapped to exon structure

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the 'absent in controls' population criterion.

gnomAD v2.1 (exome): variant absent (search_status=absent).gnomAD v4.1 (exome): variant absent (search_status=absent).gnomAD-Canada v1.0 (HostSeq genomes): variant absent (search_status=absent).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP7 supporting Benign

Met (supporting): synonymous p.Ser988= with SpliceAI max delta 0.01, far below the 0.2 impact threshold, predicting no splice effect.

spliceai: SpliceAI max delta score 0.01 (DS_AG 0.01, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0) for NM_006231.4:c.2964G>T (SpliceAI Lookup, Broad Institute, distance=500, basic mode); below the 0.2 high-impact delta threshold (Jaganathan et al. 2019, PMID 30661751), predicting no splice impact and no new splice-site creation.pvs1_variant_assessment: consequence_class='synonymous', protein NP_006222.2:p.(Ser988=), canonical_splice_consensus=false.generic_acmg_combination_rules: BP7 criterion from Richards et al. 2015 (PMID 25741868) - synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no de novo occurrence with confirmed parental testing is documented in ClinVar or the literature.

PS3 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.

PS4 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.

PM3 Not assessed: no proband genotype or phase data exist to evaluate a trans configuration with a pathogenic variant.

PM6 Not assessed: no de novo occurrence, with or without parentage confirmation, is documented for this variant.

PP1 Not assessed: no segregation study or family testing data exists — zero informative meioses are documented.

PP3 Not met: SpliceAI predicts no splice impact (max delta 0.01), the only predictor available, so no computational evidence supports a deleterious effect.

PP4 Not assessed: no proband phenotype or family-history data for a carrier of this variant is available.

PP5 Not met: no ClinVar expert-panel (3-star) pathogenic classification exists; the only submission is a 1-star laboratory 'Likely benign'.

Benign

BA1 Not met: the variant is absent (frequency 0) from gnomAD v2.1, v4.1, and gnomAD-Canada, so no population threshold is exceeded.

BS1 Not met: observed frequency is 0 in all three population databases, the opposite of a frequency greater than expected.

BS2 Not met: no healthy adult carriers or homozygotes are observed; the variant is absent from all three population databases.

BS3 Not assessed: no functional studies of this variant exist; in silico and population data cannot substitute for them.

BS4 Not assessed: no affected family member has been tested and reported as not carrying the variant.

BP2 Not assessed: no genotype data exists to establish a trans or cis configuration with a pathogenic variant.

BP4 Not met: the only 'no impact' prediction (SpliceAI max delta 0.01) is already counted under BP7; no independent benign computational line exists.

BP5 Not assessed: no reported carrier with an alternate molecular basis exists, so an alternate diagnosis can be neither established nor excluded.

BP6 Not met: the 'Likely benign' label is a 1-star laboratory submission, not an expert-panel classification, so BP6 does not apply.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1798204)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Rule & framework references · cited for criterion definitions, not variant evidence

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots