Disease | Ataxia-Telangiectasia |
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Inheritance | Autosomal recessive |
Prevalence (Rare/Common) | 1/100,000 (rare) |
ClinGen GCEP / GenCC Curation / BabySeq (Document the source and Date of Source’s curation) | ClinGen, Hereditary Cancer GCEP (07/27/2021) |
Clinical Validity Scoring Notes and points | | Expand |
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| title | Clinical Validity Scoring Notes and points |
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| Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, scleral, mucosal, and cutaneous telangiectasias, variable T and B cell defects, and a predisposition to malignancy including childhood onset lymphoma. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait had been used to identify distinct complementation groups for AT versus Nijmegen Breakage Syndrome (PMID: 3248383). The ATM protein is a member of the phosphatidylinositol 3-kinase family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control. There is abundant evidence published associating the ATM gene with ataxia telangiectasia, since the gene-disease relationship was first proposed by Savitsky K, et al., 1995 (PMID: 7792600). Multiple case level studies have been performed with AT patients that have variants in the ATM gene, including the reports of founder and recurrent pathogenic variants. Loss of function is the mechanism of disease. A significant amount of case-level data is available; the maximum points for genetic evidence has been reached (12 points). ATM protein expression is undetectable in the majority of AT patient cells as missense variants represent less than 10% of pathogenic variants detected. The established ATM homozygous null mouse models show several of the key phenotypes consistent with ataxia telangiectasia, including decreased mature T cells. This is a split curation as the autosomal recessive inherited disorder has unique clinical features and pattern of inheritance from the autosomal dominant inherited hereditary breast carcinoma which was curated separately (ClinGen: 9908). In summary, ATM is definitively associated with autosomal recessive ataxia telangiectasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7 Source: ClinGen, Hereditary Cancer GCEP (07/27/2021) |
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Clinical Validity Points Total | 18 Source(s): ClinGen, Hereditary Cancer GCEP (07/27/2021) |
Clinical Validity Classification | DEFINITIVE Source(s): ClinGen, Hereditary Cancer GCEP (07/27/2021) |
Molecular Mechanism | Loss of function Source(s): ClinGen, Hereditary Cancer GCEP (07/27/2021) |
Penetrance | High Source(s): PMID 27884168, ClinGen Hereditary Cancer GCEP, GeneReviews |
Age of Onset | Childhood Source(s): PMID 27884168 |
Severity | Moderate Source(s): PMID: 27884168, ClinGen Hereditary Cancer GCEP, GeneReviews |
Clinical Features (Sources) | Cerebellar ataxia, abnormal eye movements, postural instability Scleral, mucosal, and cutaneous telangiectasias Variable T and B cell defects Predisposition to malignancy including childhood onset lymphoma Chromosomal Breakage Premature aging Other: poor growth, gonadal atrophy, delayed pubertal development and insulin resistant diabetes AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. Typically normal intelligence Immunoblotting on patient sample showing absent or reduced ATM protein.
Note: Severe intellectual disability, seizures, non-progressive ataxia, or microcephaly may suggest a different condition. Examples include microcephaly, seizures, and developmental delay (MCSZ) or Nijmegen breakage syndrome. Sources: PMID: 27884168, ClinGen Hereditary Cancer GCEP, GeneReviews |
Gene SOPs & Notes | PVS1 - below descriptions are based on the default transcript NM_000051.3 NMD- (truncating, not predicted to undergo NMD) variants that impact the FAT/PI3K/FATC domain (p.1893-3056) can be granted PVS1_VeryStrong (as opposed to PVS1_Strong) as the recommended baseline (PMID 30192042); however, the termination codon of the variant undergoing interpretation must be 5' of p.R3047. The most 3' residue considered to be pathogenic is p.R3047, with p.Arg3047Ter interpreted as Pathogenic (Variation ID: 3029, (PMIDs: 10980530, 26628246, 19691550, 22649200, 19431188) NMD- variants that impact the HEAT domain
Source: ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer https://clinicalgenome.org/site/assets/files/7451/clingen_hbop_acmg_specifications_atm_v1_1.pdf |
Curation Summary: | The ATM gene is associated with autosomal recessive ataxia-telangiectasia, which is characterized by cerebellar ataxia scleral, mucosal, and cutaneous telangiectasias; variable T and B cell defects; predisposition to malignancy including childhood onset lymphoma; and chromosomal breakage (PMID: 27884168). Variable expression has been observed. The ATM gene is also associated with autosomal dominant hereditary breast carcinoma risk, which has been shown to increase the relative risk and absolute risk of breast cancer (PMID: 35772246). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 06/09/2023, | Jira Legacy |
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| server | System JIRA |
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| serverId | eee25142-2510-336f-918a-865682ebdf2e |
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| key | CIT-127 |
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