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.1 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%.2 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.3 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.4
Final classification
Pathogenic
PVS1PM2PM5PP5
ATM
c.67C>T
p.Arg23Ter
This variant
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.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PM5 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
ATM c.67C>T
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
vcep_suppl_tables1_pmid_40580951cspec ↗
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may be applied incorrectly, sources may be misread, and a confident-looking
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Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 8 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a nonsense change, NM_000051.3:c.67C>T (p.Arg23Ter, p.R23*), that introduces a very early premature stop codon in ATM. The ATM VCEP includes PVS1 guidance, loss of function is an established disease mechanism for ATM, and this early truncating event is consistent with full-strength PVS1 under the ATM PVS1 decision framework.
Nonsense variant p.(Arg23Ter) near the 5' end of the coding sequenceATM VCEP PVS1 guidance is availableATM loss of function is an established disease mechanism
PM2
supporting
Pathogenic
This variant is present in gnomAD v4.1 at AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles) with no homozygotes, which is below the ATM PM2 threshold of 0.001%. This rarity supports PM2 at supporting strength.
gnomAD v4.1 total AF 3.71898e-060 homozygotesATM PM2 threshold ≤0.001%
PM5
supporting
Pathogenic
This variant is a truncating variant with a premature termination codon at p.Arg23, which is far upstream of the ATM PM5 cutoff at p.Arg3047. This meets the ATM-specific PM5 supporting rule for truncating variants.
Truncating variant p.Arg23TerATM PM5 truncating-variant rule upstream of p.Arg3047
Assessed · not applied
· 3 not met · 5 not assessed
Pathogenic
PS3
Variant-specific functional literature and an ATM supplementary SNV table were identified, and the supplementary table categorized this variant as non-functional with medium-high confidence.
PS4
This variant has been reported in ClinVar and in published literature, but no case-control study or exact affected-versus-control enrichment meeting the ATM VCEP PS4 threshold was identified.
PM3
No confirmed trans observations, homozygous affected observations, or other point-scored evidence meeting the ATM PM3 framework were identified for this variant.
PP1
No segregation data were identified to show this variant tracking with disease in affected relatives under the ATM PP1 framework.
Benign
BA1
This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BA1 threshold of greater than 0.5%.
BS1
This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BS1 threshold of greater than 0.05%.
BS3
Available evidence does not support BS3.
BP2
No unaffected in-trans observations, phase-unknown benign point-scored observations, or homozygous unaffected observations meeting the ATM BP2 framework were identified for this variant.
N/A · 16
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS2 · BS4 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,613,346
0 hom · FAF 0.00037%
0 hom · FAF 0.00037%
South Asian 2 / 91,056 |
0.0022% |
European (non-Finnish) 4 / 1,179,690 |
0.00034% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.002%
· 5 / 251,364
0 hom · FAF 0.0026%
0 hom · FAF 0.0026%
South Asian 3 / 30,608 |
0.0098% |
European (non-Finnish) 2 / 113,672 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links