Classification rationale

PM2 BP4 VUS

POLE c.1924-5C>T unknown · exon 17i

PM2 supporting: the variant is extremely rare in gnomAD, with non-cancer AF 6.75776e-06. BP4 supporting: SpliceAI maximum delta 0.084 is below the <=0.1 benign threshold.

PM2 + 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 · 2 applied · 18 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v3.1 non-cancer AF is 6.75776e-06, below the <=0.0001 PM2 threshold.

gnomAD v2.1 non-cancer reports the variant as absent.gnomAD v3.1 non-cancer reports 1/147978 genome alleles, AF 6.757761288840233e-06, and zero homozygotes.Default all-comers gnomAD v2.1 reports AF 7.959692119108834e-06 and gnomAD v4.1 reports AF 4.337470040474792e-06; both report zero homozygotes.

gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

BP4 supporting Benign

Met, supporting: SpliceAI maximum delta 0.084 meets the <=0.1 BP4 supporting threshold.

The variant is intronic/splice-region, so SpliceAI is the sole applicable PP3/BP4 predictor path; REVEL is not applicable.SpliceAI reported DS_AG 0.007, DS_AL 0.084, DS_DG 0.017, and DS_DL 0.000; maximum delta 0.084.The generic SpliceAI BP4 supporting cutoff is <=0.1, from Jaganathan et al. 2019 (PMID:30661751); 0.084 meets it.

spliceai ↗

Assessed · not applied · 7 not met · 11 not assessed

Pathogenic

PVS1 Not met: c.1924-5C>T is a splice-region SNV at -5, outside the canonical ±1,2 PVS1 null-variant positions, with no demonstrated abnormal transcript or NMD.

PS2 Not assessed: no proband-parent genotypes, confirmed parentage, or documented absence of the variant in both parents are available.

PS3 Not assessed: no controlled RNA, minigene, protein, or other validated functional assay is reported for c.1924-5C>T; SpliceAI 0.084 is computational, not PS3 evidence.

PS4 Not met: the exact splice-region variant is absent from the governing recurrence tables and is not one of the specified pathogenic POLE missense hotspots.

PM3 Not assessed: no affected-proband observation, pathogenic second allele, or phase evidence establishes this variant in trans for PM3.

PM6 Not assessed: no clinical report describes this variant as de novo with unconfirmed parentage or provides supporting proband and parental data.

PP1 Not assessed: no affected relatives, informative meioses, or family segregation results are reported for this variant.

PP3 Not met: SpliceAI maximum delta 0.084 is below the >=0.2 PP3 supporting threshold.

PP4 Not assessed: no patient-level, highly specific POLE-related phenotype is available for comparison with the PP4 requirement.

PP5 Not met: ClinVar has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.

Benign

BA1 Not met: the highest reported allele frequency is 0.000201694, far below the 0.05 BA1 threshold.

BS1 Not met: the highest reported allele frequency is 0.000201694, below the generic 0.01 BS1 threshold.

BS2 Not assessed: gnomAD shows zero homozygotes, but no documented unaffected carrier or healthy-adult observation is available for BS2.

BS3 Not assessed: no controlled assay demonstrates normal splicing or protein function for c.1924-5C>T, and SpliceAI 0.084 cannot establish BS3.

BS4 Not assessed: no affected, well-phenotyped individual lacking the variant or documented non-segregation analysis is available.

BP2 Not assessed: no documented co-occurring pathogenic variant or cis/trans phase result supports BP2 for this variant.

BP5 Not assessed: no governing BP5 specification or validated BP5-specific evidence is available for this variant.

BP6 Not met: ordinary Likely benign laboratory submissions cannot trigger BP6 because ClinVar reports zero expert-panel submissions.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.33747e-06; MAF= 0.00043%, 7/1613844 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80154e-05; MAF= 0.00480%, 3/62480 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.95969e-06; MAF= 0.00080%, 2/251266 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00032583903551645487, 6/18414 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00043% · 7 / 1,613,844
0 hom · FAF 0.00044%

Remaining individuals 3 / 62,480	0.0048%
African/African American 2 / 74,932	0.0027%
East Asian 1 / 44,886	0.0022%
Admixed American 1 / 60,002	0.0017%

+ 6 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.0008% · 2 / 251,266
0 hom · FAF 0.0019%

East Asian

2 / 18,394

0.011%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.033% · 6 / 18,414
0 hom · FAF 0.2%

East Asian

6 / 1,338

0.45%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 240412)

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. 3 further PMIDs triaged but not cited — see Sources & references.

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

Triaged references · 3 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

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. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Check your email

Reset your password

Enter an access code

Your allowance