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
Final classification
Pathogenic
PVS1PM2PM5PP5
ATM
c.5515C>T
p.Gln1839Ter
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 10 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 nonsense variant introduces a premature termination codon at p.Gln1839Ter (p.Q1839*), well upstream of the 3' end of ATM, and ATM loss of function is an established disease mechanism in the applicable ATM VCEP framework. The ATM PVS1 guidance supports full-strength PVS1 for a truncating variant of this type.
ATM-specific PVS1 decision frameworkATM loss-of-function disease mechanismnonsense consequence
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an overall allele frequency of 8.674886328007367e-06 (0.00087%; 14/1613854 alleles) with 0 homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%. This supports PM2 at supporting strength.
gnomAD v2.1 absencegnomAD v4.1 rarity threshold
PM5
supporting
Pathogenic
The ATM VCEP specifies PM5_Supporting for truncating variants with a premature termination codon upstream of p.Arg3047. This variant creates p.Gln1839Ter, which is upstream of p.Arg3047, so PM5 is met at supporting strength.
ATM truncating-variant PM5 ruleprotein position p.Gln1839Ter
Assessed · not applied
· 4 not met · 6 not assessed
Pathogenic
PS3
Published studies reviewed describe ATM loss of function and radiosensitivity in affected cells more broadly, but no validated variant-specific rescue assay was identified for this variant.
PS4
This variant has been reported in ClinVar, but no case-control study, odds ratio, or exact-variant enrichment statistic meeting the ATM PS4 requirement was identified.
PM3
No confirmed observations of this variant in trans with a pathogenic ATM variant in an affected individual were identified, so PM3 cannot be assigned from the available evidence.
PP1
No segregation data were identified for this variant, so PP1 cannot be assigned.
PP3
SpliceAI predicts a maximum delta score of 0.16, which is below the ATM PP3 splicing threshold of 0.2.
Benign
BA1
The gnomAD v4.1 frequency for this variant is 0.00087%, which is far below the ATM BA1 threshold of greater than 0.5%.
BS1
The highest observed frequency remains well below the ATM BS1 threshold of greater than 0.05% in gnomAD v4.
BS3
No variant-specific assay showing rescue of ATM-specific function or radiosensitivity was identified.
BP2
No confirmed co-occurrence of this variant in trans with a pathogenic ATM variant in an unaffected individual was identified, so BP2 cannot be assigned from the available evidence.
BP4
SpliceAI predicts a maximum delta score of 0.16, which is above the ATM BP4 no-splice-impact threshold of 0.1.
N/A · 14
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · BS2 · BS4 · BP1 · BP3 · 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= 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