NM_006231.4:c.6111C>T is a synonymous POLE variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.1 The variant has been submitted to ClinVar as Likely benign by 4 clinical laboratories and as Benign by 1 clinical laboratory, supporting BP6 under the generic ACMG/AMP framework.2 Population frequency is low in gnomAD v4.1 at 4.15156e-05 (0.00415%), which is below the BS1 threshold of 0.3% and the BA1 threshold of 1.0%, so benign frequency criteria stronger than supporting are not met.3 Using the retrieved generic ACMG/AMP final classification combination rules, BP6 plus BP7 constitutes two supporting benign criteria and is consistent with a Likely benign classification.4
POLE
Final classification
Likely benign
POLE c.6111C>T · p.Ala2037=
POLE
NM_006231.4:c.6111C>T is a synonymous POLE variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.
Generic ACMG/AMP 2015 fallback using the retrieved generic_acmg_combination_rules; two supporting benign criteria were applied (BP6 and BP7), which matches the generic ACMG/AMP Likely Benign combination rule.
Classification rationale
BP6BP7
Likely benign
POLE c.6111C>T
BP6 + BP7
→
Likely benign
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 · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.15156e-05; MAF= 0.00415%, 67/1613852 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.88099e-05; MAF= 0.00988%, 9/91084 alleles, homozygotes = 0); grpmax FAF= 6.806e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.97368e-05; MAF= 0.00497%, 14/281482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228698; MAF= 0.02287%, 7/30608 alleles, homozygotes = 0); grpmax FAF= 0.00010658.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0042%
· 67 / 1,613,852
0 hom · FAF 0.0068%
0 hom · FAF 0.0068%
South Asian 9 / 91,084 |
0.0099% |
European (non-Finnish) 56 / 1,179,988 |
0.0047% |
Admixed American 1 / 60,002 |
0.0017% |
Remaining individuals 1 / 62,482 |
0.0016% |
+ 6 not observed (European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian, African/African American, Amish)
gnomAD v2.1
0.005%
· 14 / 281,482
0 hom · FAF 0.011%
0 hom · FAF 0.011%
South Asian 7 / 30,608 |
0.023% |
European (non-Finnish) 6 / 128,300 |
0.0047% |
Admixed American 1 / 35,404 |
0.0028% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV107342250, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links