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LYFE SCIENCES
Project: HERA
NM_000051.3:c.5515C>T
p.Gln1839Ter  ·  ATM
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Classification rationale
1

The ATM c.5515C>T (p.Gln1839Ter; p.Q1839*) variant has been reported in ClinVar as pathogenic, including expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 0.00087% (14/1613854 alleles) with no homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This nonsense variant introduces a premature stop codon at residue 1839, and the ATM VCEP PVS1 framework supports loss of function as a disease mechanism for ATM.

cspec ↗
4

SpliceAI predicts no strong splice effect for this variant (max delta score 0.16), which is below the ATM PP3 splicing threshold of 0.2 and above the BP4 threshold of 0.1, so computational evidence does not independently change the interpretation.

spliceai ↗ cspec ↗
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
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 8.67489e-06; MAF= 0.00087%, 14/1613854 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.18654e-05; MAF= 0.00119%, 14/1179904 alleles, homozygotes = 0); grpmax FAF= 6.89e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.652534.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53732966, n = 3 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ1839
Hotspots ↗