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LYFE SCIENCES
Project: HERA
NM_000051.3:c.67C>T
p.Arg23Ter  ·  ATM
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Classification rationale
1

The ATM c.67C>T (p.Arg23Ter, p.R23*) variant is reported in ClinVar as pathogenic, including a pathogenic expert panel classification, and it also has variant-specific cancer curation in OncoKB.

clinvar ↗ oncokb ↗
2

This variant is rare in population databases, with gnomAD v4.1 AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles; no homozygotes), which is below the ATM PM2 threshold of 0.001%.

gnomad_v4 ↗ cspec ↗
3

In an ATM supplementary SNV table, this variant was categorized as non-functional with medium-high confidence, which is consistent with a damaging loss-of-function effect, although the available summary alone does not establish ATM VCEP PS3 weighting.

cspec ↗
4

This is a nonsense variant predicted to create a very early stop codon; SpliceAI predicts no significant splice impact with a max delta score of 0.00, and the ATM computational PP3/BP4 rules are not used here because they are defined for missense or specified splicing contexts rather than truncating variants.

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
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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= 1.98915e-05; MAF= 0.00199%, 5/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.80136e-05; MAF= 0.00980%, 3/30608 alleles, homozygotes = 0); grpmax FAF= 2.596e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.71898e-06; MAF= 0.00037%, 6/1613346 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19645e-05; MAF= 0.00220%, 2/91056 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 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 = 0.00). BayesDel score = 0.60222.
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; COSV53733622, n = 9 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR23
Hotspots ↗