Classification rationale

PM2 BP7 VUS

POLE c.2172G>A

The POLE c.2172G>A (p.Ala724=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign, with five likely benign submissions and one submission of uncertain significance.¹ This variant is present at low frequency in gnomAD, with total allele frequencies of 0.00400% in v2.1 and 0.00166% in v4.1, both below the project's PM2 threshold of 0.1% and below the BS1 threshold of 0.3%.² This is a synonymous change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01; it is also not among the missense hotspot or computationally selected variants used for the custom POLE PM1, PS4, PP3, and BP4 rules.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗pvs1_variant_assessmentvcep_p_a_t_h___2_5_0___3_2_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4

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 · 16 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 moderate review Pathogenic

Population frequency is below the project's PM2 threshold of 0.1% in both gnomAD v2.1 and gnomAD v4.1. The observed total allele frequency is 0.00400% in v2.1 (10/249782 alleles) and 0.00166% in v4.1 (26/1568268 alleles), which is below the 0.1% threshold.

gnomAD v2.1 total AF=4.00349e-05 (0.00400%).gnomAD v4.1 total AF=1.65788e-05 (0.00166%).

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting review Benign

This is a synonymous variant, p.(Ala724=), with no amino-acid change. It is not a canonical splice consensus variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7.

Protein consequence is p.(Ala724=).pvs1_variant_assessment reports canonical_splice_consensus=false.SpliceAI max delta score=0.01.

spliceai ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 No confirmed de novo data with parental testing were identified, so PS2 could not be assessed.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 could not be assessed.

PS4 This variant has not been reported in COSMIC, and it is not one of the exact recurrent pathogenic missense variants eligible for the custom POLE PS4 rule.

PM1 This is a synonymous variant, p.(Ala724=), and it is not one of the exact POLE missense hotspot or recurrent exonuclease-domain variants specified in the custom POLE PM1 framework.

PM3 No data on allelic phase with another pathogenic variant were identified, so PM3 could not be assessed.

PM6 No assumed de novo data without confirmed parentage were identified, so PM6 could not be assessed.

PP1 No segregation data were identified, so PP1 could not be assessed.

PP3 This synonymous variant is not eligible for the custom POLE PP3 rule, which is restricted to exact missense variants listed in the León-Castillo supplementary computational tables.

PP4 No phenotype or family history data sufficiently specific for POLE-related disease were identified, so PP4 could not be assessed.

Benign

BA1 Population frequency does not reach the BA1 threshold of 1%.

BS1 Population frequency does not exceed the BS1 threshold of 0.3%.

BS2 Although this variant is present in population databases, no disease-specific evidence was identified to show observation in unaffected individuals is sufficient to support BS2.

BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 could not be assessed.

BS4 No evidence showing lack of segregation with disease in affected family members was identified, so BS4 could not be assessed.

BP2 No phase data or observations with another variant were identified, so BP2 could not be assessed.

BP5 No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed.

N/A · 10 PVS1 · PS1 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP4 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.65788e-05; MAF= 0.00166%, 26/1568268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000204109; MAF= 0.02041%, 15/73490 alleles, homozygotes = 0); grpmax FAF= 0.00012516.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.00349e-05; MAF= 0.00400%, 10/249782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000326878; MAF= 0.03269%, 8/24474 alleles, homozygotes = 0); grpmax FAF= 0.00015631.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0017% · 26 / 1,568,268
0 hom · FAF 0.013%

African/African American 15 / 73,490	0.02%
Remaining individuals 6 / 60,434	0.0099%
South Asian 2 / 84,082	0.0024%
East Asian 1 / 44,028	0.0023%
Admixed American 1 / 54,054	0.0019%
European (non-Finnish) 1 / 1,155,980	8.7e-05%

+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.004% · 10 / 249,782
0 hom · FAF 0.016%

African/African American 8 / 24,474	0.033%
South Asian 1 / 23,484	0.0043%
Admixed American 1 / 29,764	0.0034%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

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

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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 ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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