NM_006231.4:c.2468+16_2468+21dup is an intronic duplication in intron 21 of POLE, located at positions +16 to +21 downstream of exon 21. This variant is absent from ClinVar and has not been reported in COSMIC or the published literature in association with disease.1 The variant is present in gnomAD at very low frequency (v2.1 AF = 0.0078%, v4.1 AF = 0.0079%) with no homozygotes observed, meeting PM2 at supporting strength.2 SpliceAI predicts no splicing impact (max delta = 0.02), meeting BP4 at supporting strength.3 The custom POLE framework criteria (PM1, PS4, PP3, BP4 via León-Castillo et al. 2020) are missense-specific and do not apply to this intronic duplication.4 PVS1 is not applicable as the variant is outside the canonical splice consensus and does not meet null-variant criteria per ClinGen PVS1 framework.5 With only PM2_Supporting and BP4_Supporting applied, evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a variant of uncertain significance (VUS).6
POLE
Final classification
VUS
POLE c.2468+16_2468+21dup · p.?
POLE
NM_006231.4:c.2468+16_2468+21dup is an intronic duplication in intron 21 of POLE, located at positions +16 to +21 downstream of exon 21.
The León-Castillo et al. 2020 custom POLE framework provides standard ACMG/AMP 2015 final combination rules. Only two criteria are met: PM2 at supporting strength (pathogenic) and BP4 at supporting strength (benign). This combination of one pathogenic supporting and one benign supporting criterion satisfies no pathogenic, likely pathogenic, benign, or likely benign rule in the framework. The conflicting evidence defaults to VUS per ACMG/AMP 2015.
Classification rationale
PM2
BP4
VUS
POLE c.2468+16_2468+21dup
PM2 + BP4
→
VUS
4
vcep_path_250_323
6
generic_acmg_combination_rules
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= 7.89609e-05; MAF= 0.00790%, 127/1608390 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000350795; MAF= 0.03508%, 21/59864 alleles, homozygotes = 0); grpmax FAF= 0.00023458.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.81511e-05; MAF= 0.00782%, 22/281506 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277855; MAF= 0.02779%, 2/7198 alleles, homozygotes = 0); grpmax FAF= 5.709e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0079%
· 127 / 1,608,390
0 hom · FAF 0.023%
0 hom · FAF 0.023%
Admixed American 21 / 59,864 |
0.035% |
African/African American 13 / 74,716 |
0.017% |
Remaining individuals 10 / 62,242 |
0.016% |
European (non-Finnish) 80 / 1,175,914 |
0.0068% |
East Asian 1 / 44,612 |
0.0022% |
South Asian 2 / 90,908 |
0.0022% |
+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0078%
· 22 / 281,506
0 hom · FAF 0.0057%
0 hom · FAF 0.0057%
Remaining individuals 2 / 7,198 |
0.028% |
Admixed American 5 / 35,350 |
0.014% |
African/African American 3 / 24,922 |
0.012% |
European (non-Finnish) 10 / 128,384 |
0.0078% |
East Asian 1 / 19,904 |
0.005% |
South Asian 1 / 30,584 |
0.0033% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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.
Sources & reference links