NM_000051.4:c.9047_9057delAACTGAAAGGA
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000051.4(ATM):c.9047_9057delAACTGAAAGGA(p.Lys3016SerfsTer43) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.9047_9057delAACTGAAAGGA | p.Lys3016SerfsTer43 | frameshift_variant | Exon 63 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
The c.9047_9057del;p.(Lys3016Serfs*?) is a null frameshift variant (NMD) in the ATM gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 142954)PS4. This variant is not present in population databases (rs587782847- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
This sequence change results in a frameshift in the ATM gene (p.Lys3016Serfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the ATM protein and extend the protein by 1 additional amino acid residues. 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: 142954). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 18813293, 19691550, 19781682, 23532176, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.9047_9057del11 pathogenic mutation, located in coding exon 62 of the ATM gene, results from a deletion of 11 nucleotides between nucleotide positions 9047 and 9057, causing a translational frameshift with a predicted alternate stop codon (p.K3016Sfs*43). This deletion and subsequent frameshift occur near the 3' terminus of ATM and results in the elongation of the protein by 2 amino acids. This frameshift alters the sequence of ATM's FATC domain, a domain important for activation of ATM's kinase activity by DNA damage (Sun Y et al. Mol. Cell. Biol. 2007 Dec;27(24):8502-9; Jiang XJ et al. Biol. Chem. 2006 Jun;281(23):15741-6). As such, this alteration is interpreted as a disease-causing mutation. -
This variant deletes 11 nucleotides in exon 63 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
Familial cancer of breast Pathogenic:2
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This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15039971, 21965147]. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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See cases Pathogenic:1
ACMG classification criteria: PVS1, PS4, PM2 -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual undergoing panel testing due to suspected hereditary breast and ovarian cancer syndrome (PMID: 33047316); This variant is associated with the following publications: (PMID: 28152038, 15039971, 21965147, 33047316) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at