Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis variant changes 1 nucleotide in exon 37 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with ataxia-telangiectasia (PMID: 9792409, 10873394, 15928302, 22213089, 22649200). One family was reported to have two individuals carrying this variant who were affected with ataxia-telangiectasia (PMID: 22213089). Functional studies in cells derived from an individual affected with ataxia-telangiectasia (carrying this variant and ATM IVS16-1G>C) showed no protein expression and no kinase activity (PMID: 22649200). This variant has been detected in several individuals affected with breast cancer (PMID: 28779002, 35365198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The p.Q1839* pathogenic mutation (also known as c.5515C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5515. This changes the amino acid from a glutamine to a stop codon within coding exon 36. This pathogenic mutation was detected along with a second ATM gene mutation in a Dutch patient with ataxia telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7). This alteration has also been reported in 1/13087 breast cancer cases and 0/5488 control individuals in the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
This sequence change creates a premature translational stop signal (p.Gln1839*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with ataxia telangiectasia (PMID: 9792409, 10873394, 15928302, 22213089, 22649200). ClinVar contains an entry for this variant (Variation ID: 189177). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
"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."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: ATMQ1839*ATMQ1839*SomaticNCBI Gene:472|Show additional gene information Variant OverviewATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.The ATM Q1839* is a truncating mutation in a tumor suppressor gene, and therefore is likely oncogenic.Hide mutation effect description The mutation effect description for truncating mutations in ATM is: ATM truncating mutations can produce several forms of C-terminally truncated ATM proteins. When found in the germline, these mutations result in ataxia-telangiectasia syndrome, which increases cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers (PMID: 27413114). Deletion of ATM in mouse models and cell lines demonstrates that it is oncogenic as measured by decreased DNA repair efficiency and increased cellular motility (PMID: 30553448, 30348496). JAX-CKB: ATM Q1839* results in a premature truncation of the Atm protein at amino acid 1839 of 3056 (UniProt.org). Q1839* fails to rescue survival and proliferation of ATM-haploid cells upon olaparib treatment in a high-throughput cell culture assay (PMID: 40580951), and therefore, is predicted to lead to a loss of Atm protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.06 | -18 bp |
| Donor Loss (DL) | 0.01 | 159 bp |
| Acceptor Gain (AG) | 0.16 | 43 bp |
| Donor Gain (DG) | 0.0 | -19 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)