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 deletes two bases in exon 34 of the ATM mRNA (c.5075_5076del), causing a frameshift after codon 1692. This creates a premature translational stop signal 9 amino acid residues later p.(Lys1692Argfs*9) and 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). Based on the classification criteria set by the ACMG and AMP (PMID:25741868) this variant has been classified as likely pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ATM K1692Rfs*9 variant is a truncating mutation in the ATM gene, which is involved in the DNA damage response. Functional evidence indicates 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, as demonstrated in mouse models and cell lines.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.32 | -67 bp |
| Donor Loss (DL) | 0.09 | 104 bp |
| Acceptor Gain (AG) | 0.03 | -13 bp |
| Donor Gain (DG) | 0.0 | -117 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Null Variant (nonsense, frameshift, etc.) in a gene where loss-of-function is a known mechanism of disease". The evidence for this variant shows it is a frameshift (K1692Rfs*9) predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength because it is a null variant in ATM, a gene with LOF mechanism.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as an established pathogenic variant regardless of nucleotide change." The evidence shows this is a frameshift, not the same amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo in a patient with the disease and no family history." There are no de novo data. Therefore, this criterion is not applied.
PS3 (Supporting)
According to VCEP guidelines, the rule for PS3 Supporting is: "Use when a variant fails to rescue an ATM‐specific feature only (e.g. phosphorylation of ATM‐specific targets)." The evidence shows decreased DNA repair efficiency in functional studies, indicating failure to rescue ATM-specific DNA repair function. Therefore, this criterion is applied at Supporting strength.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals is significantly increased compared to controls." No case‐control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or functional domain without benign variation." This frameshift is not within a defined hotspot or domain. 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." The evidence shows zero observations in gnomAD (allele count = 0, frequency = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." No evidence of trans configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame indels or stop‐loss variants." This variant causes a frameshift with stop‐gain, not an in‐frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." This is a frameshift variant, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity." No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variants where missense is a common mechanism." This is a truncating variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "RNA: At least one well‐established in silico predictor shows impact on splicing; Protein: REVEL >0.7333." SpliceAI score is 0.32 and no REVEL data. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype or family history highly specific for gene." No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic but evidence is unavailable." ClinVar lists this variant as Likely Pathogenic by one clinical lab. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency >5% in controls." Frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency too high for disorder." Frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adults." No such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 Supporting is: "Variant rescues either an ATM-specific feature or radiosensitivity." No rescue data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members." No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." This is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder." No evidence. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without a functional domain." This is frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Protein: REVEL ≤0.249; RNA: predictor shows no splicing impact." No such benign computational evidence. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis." No alternate cause data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence unavailable." No such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or deep intronic variant with no splice impact." This is frameshift. Therefore, this criterion is not applied.