Disease | Ataxia-Telangiectasia | ||||||||
|---|---|---|---|---|---|---|---|---|---|
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 | 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 | ||||||||
Clinical Validity Points Total | 18 | ||||||||
Clinical Validity Classification | DEFINITIVE | ||||||||
Molecular Mechanism | Loss of function | ||||||||
Penetrance | High | ||||||||
Age of Onset | Childhood (PMID: 27884168) | ||||||||
Severity | Moderate | ||||||||
Clinical Features (Sources) |
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 |
| ||||||||
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,
|
Disease | Hereditary Breast Carcinoma |
|---|---|
Inheritance | Autosomal dominant |
Prevalence (rare/common) | 126.9 per 100,000 women per year (Common) |
ClinGen GCEP / GenCC Curation / BabySeq (Document the source) | ClinGen Breast/Ovarian Cancer GCEP 07/12/2017 |
Clinical Validity Scoring Notes and points | Variant/Case Evidence: Segregation Evidence: Case/Control Evidence: 12 points Experimental Evidence: 6 points |
Clinical Validity Points Total |
18 points | |||||||||
Clinical Validity Classification | Definitive | ||||||||
Molecular Mechanism | Loss of function (PMID: 35772246) | ||||||||
Penetrance | Reduced | ||||||||
Age of Onset | Adulthood | ||||||||
Severity | Moderate | ||||||||
Clinical Features |
Sources: PMID: 35772246 | ||||||||
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant | ||||||||
Curation Summary: | The ATM gene is 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). The ATM gene is also 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. | ||||||||
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 06/09/2023,
|