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NM_000051.3:c.7031G>A
p.Trp2344Ter · ATM
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 · v1.5
0%
complete
Final classification
Pathogenic
PVS1PM2PM5
ATM
c.7031G>A
p.Trp2344Ter
nonsense · exon 48
Gene context NCBI Gene ↗ OncoKB ↗

ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

This variant

This truncating ATM allele is relevant to the gene's tumor-suppressor role in DNA-damage response and to ATM-associated recessive ataxia-telangiectasia and cancer predisposition.

Transcript
NM_000051.3
HGVS · transcript:coding
NM_000051.3:c.7031G>A
GRCh38
chr11:108327700 G>A
GRCh37
chr11:108198427 G>A
Pathogenic: PVS1 (very strong) plus PM2 and PM5 (supporting) satisfy Rule4 of the ATM VCEP v1.5 framework.
Classification rationale
PVS1PM2PM5 Pathogenic
ATM c.7031G>A nonsense · exon 48

Pathogenic: PVS1 very strong supports loss of function from the ATM nonsense variant p.(Trp2344Ter). Pathogenic: PM2 supporting confirms the variant is below the ATM VCEP rarity threshold in gnomAD v4.1. Pathogenic: PM5 supporting applies because the premature stop at p.Trp2344 is upstream of the ATM VCEP p.Arg3047 cutoff.

PVS1 + PM2 + PM5 → Pathogenic
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 · 3 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 · 3
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met, very strong: c.7031G>A is a nonsense exon-48 variant truncating ATM at p.Trp2344, upstream of the p.Arg3047 C-terminal caution boundary.
Case normalization identifies NM_000051.3:c.7031G>A as NP_000042.3:p.(Trp2344Ter), p.(W2344*), a nonsense variant.The ATM HBOP VCEP v1.5 PVS1 specification names NM_000051.3/ENST00000278616.8 as the default transcript and states that all exons are constitutive without major rescue isoforms.The ATM HBOP VCEP v1.5 specification states that the most 3' C-terminal residue considered pathogenic is p.Arg3047; p.Trp2344Ter is upstream of this boundary.
cspec ↗
PM2 supporting Pathogenic
Met, supporting: gnomAD v4.1 total AF 0.00006196% is below the ATM VCEP PM2 threshold of <=0.001%, with one observed allele.
ClinGen HBOP ATM VCEP v1.5 specifies PM2_Supporting at frequency <=0.001% in gnomAD v4 and states that n=1 in a single subpopulation is sufficient.gnomAD v4.1 reports total AF 6.195871319187746e-07 (0.0000619587%), 1/1,613,978 alleles, highest South Asian AF 1.098008213101434e-05 (0.001098%) from 1/91,074 alleles, and 0 homozygotes.The variant is absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records; v3.1 non-cancer is a genomes-only source.
cspec ↗gnomad_v4 ↗
PM5 supporting Pathogenic
Met, Supporting: the truncating stop at p.Trp2344 is upstream of the ATM VCEP PM5 cutoff p.Arg3047.
The ATM VCEP PM5 rule specifies Supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.The case variant is a nonsense truncation at p.Trp2344, and residue 2344 is upstream of residue 3047.The collected PM5 candidate artifact correctly identifies the governing ATM mode as truncation_cutoff_gene_specific and instructs review against the governing PM5 rule rather than classic missense PM5.
cspec ↗
Assessed · not applied · 6 not met · 4 not assessed
Pathogenic
PS3 Not assessed: direct measurement classified c.7031G>A as Non-functional with High confidence, but this assay is outside ATM VCEP-approved PS3 calibration.
PS4 Not met: no case-control odds ratio, hazard ratio, or relative risk is reported for c.7031G>A, so the ATM VCEP requirement of OR >=2 with p <=.05 is unmet.
PM3 Not assessed: no affected A-T proband, pathogenic variant in trans, or phase information is available to assign the VCEP's PM3 points.
PP1 Not assessed: no documented affected relatives or segregation results are available to meet the ATM VCEP's one-relative supporting threshold.
PP5 Not met: ClinVar's five submissions for c.7031G>A are laboratory-level with zero expert-panel assertions, so the PP5 expert-panel condition is not satisfied.
Benign
BA1 Not met: gnomAD v4.1 AF 0.00006196% is below the ATM VCEP BA1 threshold of >0.5%.
BS1 Not met: the highest reported gnomAD v4.1 subpopulation AF is 0.001098%, below the ATM VCEP BS1 threshold of >0.05%.
BS3 Not met: direct prime-editing classification was Non-functional with High confidence, not a normal ATM functional-rescue result.
BP2 Not assessed: no unaffected adult carrying this variant with a pathogenic ATM variant in trans is documented for the VCEP's BP2 scoring.
BP6 Not met: ClinVar has no expert-panel benign or likely benign assertion for c.7031G>A, so the BP6 expert-panel condition is not satisfied.
N/A · 15 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS2 · BS4 · BP1 · BP3 · BP4 · BP5 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19587e-07; MAF= 0.00006%, 1/1613978 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09801e-05; MAF= 0.00110%, 1/91074 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05% · 1 / 1,613,978
0 hom
South Asian
1 / 91,074
0.0011%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2679782)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). BayesDel score = 0.655873.
SpliceAI ↗
Functional / OncoKB screenshot
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
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.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
27413114 ↗ ATM Mutations in Cancer: Therapeutic Implications. ONCOKB
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
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR
31479213 ↗ PMID 31479213 CLINVAR