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LYFE SCIENCES
Project: HERA
NM_006231.4:c.2172G>A
p.Ala724=  ·  POLE
León-Castillo et al. 2020 custom POLE framework · vleon-castillo-2020-custom-framework-v1
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Classification rationale
1

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.

clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA724
Hotspots ↗