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 sequence change creates a premature translational stop signal (p.Gly2772Glufs*34) 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 variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 2506475). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ATM G2772Efs*34 variant is a truncating mutation in the ATM gene, which is a tumor suppressor involved in the DNA damage response. Functional studies indicate that truncating mutations in ATM can lead to the production of C-terminally truncated proteins, resulting in decreased DNA repair efficiency and increased cellular motility. These effects support the variant's oncogenic potential. Additionally, germline truncating mutations in ATM are associated with ataxia-telangiectasia syndrome, which predisposes individuals to various cancers.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.14 | -44 bp |
| Donor Loss (DL) | 0.14 | 105 bp |
| Acceptor Gain (AG) | 0.0 | 3 bp |
| Donor Gain (DG) | 0.0 | -7 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength." The evidence for this variant shows: a frameshift deletion (c.8315del) predicted to cause a premature termination codon upstream of the last exon, leading to nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in ATM and meets the VCEP PVS1 decision tree for LoF.
PS1 (Not Applied)
According to ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant regardless of nucleotide change (strong)." The evidence for this variant shows: a novel frameshift deletion, not a recurring missense change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo parental testing data. Therefore, this criterion is not applied.
PS3 (Supporting)
According to VCEP guidelines, the rule for PS3 Supporting is: "Supporting Strength: Use when a variant fails to rescue an ATM specific feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency." The evidence for this variant shows: in vitro studies demonstrate reduced ATM-mediated DNA repair efficiency, an ATM-specific functional defect. There are no data on radiosensitivity rescue. Therefore, this criterion is applied at Supporting strength because the variant fails to rescue an ATM-specific feature per VCEP PS3_Supporting.
PS4 (Not Applied)
According to ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals statistically increased over controls (case–control data)." The evidence for this variant shows: no case–control or cohort data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no specific hotspot or domain annotation. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 Supporting is: "Frequency ≤ 0.001% if n = 1 in a single subpopulation; PM2_supporting applies." The evidence for this variant shows: absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls per VCEP PM2_Supporting.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Allelic data for recessive disorders (ATM ataxia-telangiectasia) using PM3/BP2 table." The evidence for this variant shows: no information on trans configuration or compound heterozygosity. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: frameshift leading to early stop, not a stop-loss or in-frame change. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5_Supporting is: "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047." The evidence for this variant shows: PTC at codon 2806, upstream of p.R3047. Therefore, this criterion is applied at Supporting strength because the truncation is upstream of the defined codon per VCEP PM5_Supporting.
PM6 (Not Applied)
According to ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo reports. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism." The evidence for this variant shows: a frameshift, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: SpliceAI scores below threshold and no missense prediction. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no detailed phenotype information. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar submissions exist but ACMG/ClinGen discourages reliance on PP5. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to ACMG guidelines, the rule for BA1 is: "Allele frequency > 5% in control populations." The evidence for this variant shows: absent from controls. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to ACMG guidelines, the rule for BS1 is: "Allele frequency greater than expected for disorder." The evidence for this variant shows: absent from controls. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals with full penetrance expected." The evidence for this variant shows: no such observation. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Moderate/Supporting if variant rescues ATM-specific features or radiosensitivity." The evidence for this variant shows: functional data demonstrate loss of function, not rescue. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Allelic data for recessive disorders (ATM) using PM3/BP2 table." The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions." The evidence for this variant shows: frameshift outside known repeat. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: frameshift with clear LoF mechanism. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: no benign source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to ACMG guidelines, the rule for BP7 is: "Synonymous variants with no splicing impact." The evidence for this variant shows: frameshift, not synonymous. Therefore, this criterion is not applied.