The ATM NM_000051.3:c.5681_5682del (NP_000042.3:p.(Glu1894AlafsTer9); p.(E1894Afs*9)) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06; 0 homozygotes), which is below the ATM PM2_Supporting threshold of 0.001% and well below the BS1 and BA1 thresholds.2 The variant is a frameshift predicted to truncate ATM at codon 1894, and under the ATM VCEP framework this supports PVS1 because loss of function is an established disease mechanism for ATM; the ATM-specific PM5 truncation rule also applies because the premature termination is upstream of p.Arg3047.3 SpliceAI predicts no significant splice effect for this variant (maximum delta score 0.14), which is below the ATM PP3 splice threshold of 0.2 and above the BP4 benign splice threshold of 0.1.4
Final classification
Pathogenic
PVS1PM2PM5PP5
ATM
c.5681_5682del
p.Glu1894AlafsTer9
This variant
The ATM NM_000051.3:c.5681_5682del (NP_000042.3:p.(Glu1894AlafsTer9); p.(E1894Afs*9)) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
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.5681_5682del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
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 variant is a frameshift, NM_000051.3:c.5681_5682del, predicted to cause p.(Glu1894AlafsTer9) [p.(E1894Afs*9)]. The ATM VCEP includes gene-specific PVS1 guidance, loss of function is an established disease mechanism for ATM, and this truncating change is not at the extreme 3′ end, supporting PVS1 at very strong strength.
Frameshift consequencePredicted premature termination after 9 altered amino acidsATM loss of function established as disease mechanism
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06, 0.00019%; highest observed population AF 1.60149e-05, 0.00160%; 0 homozygotes), which is below the ATM VCEP PM2_Supporting threshold of 0.001%.
Absent from gnomAD v2.13/1612956 alleles in gnomAD v4.1Highest observed population AF 1.60149e-05
PM5
supporting
Pathogenic
Under the ATM VCEP framework, PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047. This frameshift produces p.(Glu1894AlafsTer9), which is upstream of p.Arg3047, so PM5 is met at supporting strength.
ATM-specific truncation-cutoff PM5 ruleProtein consequence p.(Glu1894AlafsTer9) upstream of p.Arg3047PM5 candidate review confirms non-classic truncation mode
Assessed · not applied
· 4 not met · 6 not assessed
Pathogenic
PS3
No variant-specific functional study was identified that showed this exact variant failed to rescue an ATM-specific feature or failed to rescue both an ATM-specific feature and radiosensitivity, which is required by the ATM VCEP framework for PS3.
PS4
ClinVar reports this variant in germline disease databases, but no case-control study or quantified enrichment data meeting the ATM VCEP PS4 threshold were identified.
PM3
Published and database observations suggest this variant has been seen in individuals with ataxia-telangiectasia, but the retrieved evidence did not establish confirmed in trans occurrence with a pathogenic ATM variant, phase-unknown point totals, or qualifying homozygous evidence needed to score PM3 under the ATM point-based framework.
PP1
No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 could not be applied.
PP3
For ATM, PP3 for splicing requires SpliceAI at least 0.2.
Benign
BA1
The highest observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is far below the ATM BA1 threshold of greater than 0.5%, so BA1 is not met.
BS1
The highest observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is below the ATM BS1 threshold of greater than 0.05%, so BS1 is not met.
BS3
No variant-specific functional study was identified showing this exact variant rescued an ATM-specific feature or radiosensitivity, which is required by the ATM VCEP framework for BS3.
BP2
No qualifying evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, so BP2 could not be applied.
BP4
For ATM, BP4 for splicing requires SpliceAI 0.1 or lower.
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= 1.85994e-06; MAF= 0.00019%, 3/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60149e-05; MAF= 0.00160%, 1/62442 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,612,956
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
Remaining individuals 1 / 62,442 |
0.0016% |
European (non-Finnish) 2 / 1,179,252 |
0.00017% |
+ 8 not observed (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 (4 clinical laboratories) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 407525)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
30348496 ↗
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
ONCOKB
30553448 ↗
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
ONCOKB
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR