rs587781598
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.1290_1291delTG(p.Cys430fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,605,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
ATM
NM_000051.4 frameshift
NM_000051.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.105
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-108250752-CTG-C is Pathogenic according to our data. Variant chr11-108250752-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.1290_1291delTG | p.Cys430fs | frameshift_variant | 10/63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
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GnomAD3 genomes 0.00000669 AC: 1AN: 149514Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250386Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135368
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1455664Hom.: 0 AF XY: 0.00000967 AC XY: 7AN XY: 724224
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2025 | This sequence change creates a premature translational stop signal (p.Cys430*) 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 present in population databases (rs587781598, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 23143971). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2021 | Variant summary: ATM c.1290_1291delTG (p.Cys430X) 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 allele was found at a frequency of 4e-06 in 250386 control chromosomes. c.1290_1291delTG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic_1998, Worth_2013, Li_2000). One patient had mild AT, despite functional analysis of LCL and fibroblasts from this individual revealing absent ATM kinase activity, absent ATM protein expression, and increased radiosensitivity (Worth_2013). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 02, 2021 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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; This variant is associated with the following publications: (PMID: 23143971, 9463314, 10817650, 28152038, 28779002, 31980526, 29922827, 35626031, 37024097) - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 16, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
ATM-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2023 | The ATM c.1290_1291delTG variant is predicted to result in premature protein termination (p.Cys430*). This variant has been reported in multiple individuals with autosomal recessive ataxia telangiectasia (Table 1, Stankovic et al. 1998. PubMed ID: 9463314; Worth et al. 2012. PubMed ID: 23143971) or autosomal dominant susceptibility to breast and/or ovarian cancer (Table S2, Espinel et al. 2022. PubMed ID: 35626031). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141241/). An in vitro experimental study suggests this variant increases cells radiosensitivity (Figure 2, Worth et al. 2012. PubMed ID: 23143971). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 07, 2024 | The c.1290_1291delTG pathogenic mutation (also known as p.C430*), located in coding exon 9 of the ATM gene, results from a deletion of 2 nucleotides between positions 1290 and 1291. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This alteration was reported in conjunction with a second pathogenic alteration in an ataxia-telangiectasia family (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45). This alteration has also been reported in a woman with a mild ataxia-telangiectasia presentation in conjunction with a second pathogenic alteration. Functional analyses of LCL and fibroblasts from this individual revealed absent ATM kinase activity, absent ATM protein expression, and increased radiosensitivity (Worth et al. Mov. Disord. 2013 Apr;28(4):524-8). 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. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at