Classification rationale

BP4 VUS

POLE c.6331-24C>T unknown · exon 45i

BP4 supporting: SpliceAI max delta 0.076 is below the <=0.1 threshold, so no splice-altering effect is predicted for this intronic variant. VUS: the single supporting benign criterion (BP4) does not satisfy the Likely Benign rule requiring a strong plus supporting benign criterion or two supporting benign criteria.

BP4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting: SpliceAI max delta 0.076, at or below the <=0.1 BP4 threshold.

Variant consequence type settled first: c.6331-24C>T is intronic and non-canonical (outside ±1,2 splice consensus positions), so BP4 was evaluated only through the SpliceAI path and no missense predictor (REVEL) was used; the prefetch confirms REVEL 'found: false' and BayesDel 'found: false' for this variant.SpliceAI Lookup (hg37, distance 500, basic annotation, masked, source_data.spliceai_available true) returned DS_AG 0.004, DS_AL 0.028, DS_DG 0.076, DS_DL 0.001, max_delta_score 0.076, compared against the Jaganathan et al. 2019 Cell cutoff supplied for this task (BP4 supporting <= 0.1; PMID:30661751).Pangolin scores from the same lookup (SG 0.044, SL -0.014) independently show no predicted splice gain or loss.

spliceai ↗PMID:25741868 ↗

Assessed · not applied · 9 not met · 10 not assessed

Pathogenic

PVS1 Not met: the intronic c.6331-24C>T (24 bp from the exon 46 acceptor) has SpliceAI max delta 0.076, below the 0.2 supporting cutoff, so no null effect is predicted.

PS2 Not assessed: no proband or parental genotypes are available to establish a confirmed de novo occurrence.

PS3 Not assessed: no functional or RNA assay of POLE c.6331-24C>T exists; SpliceAI 0.076 and the absent REVEL score are in-silico only.

PS4 Not met: intronic c.6331-24C>T is absent from the POLE recurrent-variant table (Supplementary Table S1) and no case-control enrichment statistic exists.

PM1 Not met: c.6331-24C>T is intronic (intron 45, p.?) and outside every POLE exonuclease-domain hotspot (P286R, V411L, S297F, A456P, S459F).

PM2 Not met: total allele frequency 0.000237 (gnomAD v2.1, 66/278,448 alleles) exceeds the 0.0001 PM2 rarity threshold in all four datasets.

PM3 Not assessed: no second POLE variant, zygosity or phase is documented and gnomAD reports zero homozygotes in v2.1 (66/278,448) and v4.1 (209/1,611,370) alleles, leaving an in-trans configuration untested.

PM6 Not assessed: no proband carrying the variant is documented, so no assumed de novo occurrence can be recorded.

PP1 Not assessed: no pedigree or affected-relative genotypes provide any co-segregation data for this variant.

PP3 Not met: SpliceAI max delta 0.076 vs the >=0.2 supporting threshold for PP3.

PP4 Not assessed: no phenotype or family-history data for the proband were available, so disease specificity could not be evaluated.

PP5 Not met: the only ClinVar record for this exact variant is a single-submitter, 1-star laboratory assertion, not an expert-panel pathogenic classification.

Benign

BA1 Not met: highest population frequency 0.00053 (gnomAD v2.1 non-cancer exomes, non-Finnish European) versus the BA1 stand-alone threshold of 0.05.

BS1 Not met: highest observed frequency 0.00053 versus the generic BS1 threshold of 0.01, about 19-fold below and 8/8 dataset values under 0.001.

BS3 Not assessed: no functional assay demonstrates preserved POLE splicing or proofreading; SpliceAI 0.076 and the absent REVEL score are in-silico only.

BS4 Not assessed: no affected family members were genotyped, so lack of segregation cannot be demonstrated for this variant.

BP2 Not assessed: no documented co-occurring pathogenic POLE allele and no phase data, with zero homozygotes reported in gnomAD v2.1 (66/278,448) and v4.1 (209/1,611,370) alleles, so no cis or trans configuration can be evaluated.

BP5 Not assessed: no case-level data were available to determine whether the variant co-occurs with an alternate molecular basis for disease.

BP6 Not met: the exact-variant ClinVar Likely benign label comes from one non-expert laboratory (1 star, zero expert-panel submissions), which cannot trigger BP6.

N/A · 8 PS1 · PM4 · PM5 · PP2 · BS2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000129703; MAF= 0.01297%, 209/1611370 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000163774; MAF= 0.01638%, 193/1178456 alleles, homozygotes = 0); grpmax FAF= 0.00014455.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000237028; MAF= 0.02370%, 66/278448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00048502; MAF= 0.04850%, 61/125768 alleles, homozygotes = 0); grpmax FAF= 0.00044857.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.013% · 209 / 1,611,370
0 hom · FAF 0.014%

European (non-Finnish) 193 / 1,178,456	0.016%
European (Finnish) 6 / 63,024	0.0095%
Remaining individuals 5 / 62,420	0.008%
Admixed American 2 / 60,020	0.0033%
South Asian 2 / 91,026	0.0022%
African/African American 1 / 74,996	0.0013%

+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.024% · 66 / 278,448
0 hom · FAF 0.045%

European (non-Finnish) 61 / 125,768	0.049%
European (Finnish) 4 / 24,970	0.016%
Admixed American 1 / 35,310	0.0028%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)

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 = 1697379)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

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

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

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