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
ATM
Final classification
Pathogenic
ATM c.67C>T · p.Arg23Ter
ATM
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 ↗
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 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