rs1555097650
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.4358_4359del(p.Ile1453LysfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D1452D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4358_4359del | p.Ile1453LysfsTer37 | frameshift_variant | 29/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4358_4359del | p.Ile1453LysfsTer37 | frameshift_variant | 29/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727026
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 03, 2023 | Variant summary: ATM c.4358_4359delTA (p.Ile1453LysfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251162 control chromosomes. c.4358_4359delTA has been reported in the literature in an individual affected with Ataxia-Telangiectasia (Birrell_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 10, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 29, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551030). This variant is also known as c.4355_4356delAT. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 15880721). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1453Lysfs*37) 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). - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 24, 2024 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 11, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 26, 2021 | The c.4358_4359delTA pathogenic mutation, located in coding exon 28 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 4358 to 4359, causing a translational frameshift with a predicted alternate stop codon (p.I1453Kfs*37). This alteration was identified in an individual diagnosed with ataxia telangiectasia (Birrell GW et al. Hum Mutat, 2005 Jun;25:593). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as c.4355_4356delAT in published literature. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at