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

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

POLE NM_006231.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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