The ATM c.5515C>T (p.Gln1839Ter; p.Q1839*) variant has been reported in ClinVar as pathogenic, including expert panel review.1 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%.2 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.3 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.4
ATM
Final classification
Pathogenic
ATM c.5515C>T · p.Gln1839Ter
ATM
The ATM c.5515C>T (p.Gln1839Ter; p.Q1839*) variant has been reported in ClinVar as pathogenic, including expert panel review.
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.5515C>T
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessment
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= 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.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00087%
· 14 / 1,613,854
0 hom · FAF 0.00069%
0 hom · FAF 0.00069%
European (non-Finnish) 14 / 1,179,904 |
0.0012% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.652534.
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; COSV53732966, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links