The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.1 gnomAD v4.1 likewise shows a total AF of 1.44198e-05 (0.00144%) and grpmax FAF 3.005e-05, which remains below the generic PM2 rarity threshold of 0.1% and confirms that the variant is uncommon in the general population.2 SpliceAI predicts minimal splicing effect, with a maximum delta score of 0.03, which is below the splice-impact threshold of 0.2 and supports BP4.3 ClinVar contains a likely benign classification for this variant with single-submitter review status, which is concordant with a benign leaning but is not used as stand-alone classification evidence.4 Because the available data provide one supporting pathogenic criterion for rarity and one supporting benign criterion for computational evidence against splice disruption, NM_006231.4:c.4006-15C>T is classified as a variant of uncertain significance.
POLE
Final classification
VUS
POLE c.4006-15C>T · p.?
POLE
The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.
Conflicting supporting evidence under generic ACMG/AMP: PM2 is met for rarity and BP4 is met for benign computational splicing evidence.
Classification rationale
PM2
BP4
VUS
POLE c.4006-15C>T
PM2 + BP4
→
VUS
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= 1.44198e-05; MAF= 0.00144%, 21/1456334 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.98519e-05; MAF= 0.00699%, 6/85896 alleles, homozygotes = 0); grpmax FAF= 3.005e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.04127e-05; MAF= 0.00204%, 5/244946 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.77552e-05; MAF= 0.00878%, 3/34186 alleles, homozygotes = 0); grpmax FAF= 2.326e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014%
· 21 / 1,456,334
0 hom · FAF 0.003%
0 hom · FAF 0.003%
South Asian 6 / 85,896 |
0.007% |
Admixed American 3 / 44,452 |
0.0067% |
Remaining individuals 2 / 60,188 |
0.0033% |
African/African American 1 / 33,410 |
0.003% |
European (non-Finnish) 9 / 1,110,426 |
0.00081% |
+ 4 not observed (European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian)
gnomAD v2.1
0.002%
· 5 / 244,946
0 hom · FAF 0.0023%
0 hom · FAF 0.0023%
Admixed American 3 / 34,186 |
0.0088% |
South Asian 2 / 30,214 |
0.0066% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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