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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

Expand
titleClinical 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

Source: ClinGen, Hereditary Cancer GCEP (07/27/2021)

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 ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer has ATM specific rules. Commonly used ones are highlighted here for reference: 

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.

PM5_Supporting can be applied for NMD- variants whose termination is upstream of p.R3047. The most 3'

residue considered to be

pathogenic variant 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

PM2_Supporting - Rare is considered ≤.001% in all subpopulations where N is >1.

BA1 >0.5% (filtering allele frequency)

BS1 >0.05% (filtering allele frequency)

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
serverSystem JIRA
serverIdeee25142-2510-336f-918a-865682ebdf2e
keyCIT-127

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

Source: ClinGen Breast/Ovarian Cancer GCEP 07/12/2017

Clinical Validity Points Total

18 points

Clinical Validity Classification

Definitive

Source: ClinGen Breast/Ovarian Cancer GCEP 07/12/2017

Molecular Mechanism

Loss of function (PMID: 35772246)

Penetrance

Reduced

Age of Onset

Adulthood

Severity

Moderate

Clinical Features

  • Moderately increased breast cancer risk (estimated relative risk of 2.8% (90% CI, 2.2 to 3.7), and an absolute BC risk by 80 years of age of 27%) PMID: 35772246

  • Increased risks of prostate, pancreatic, and ovarian cancers.

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 variantSEE ABOVE

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,

Jira Legacy
serverSystem JIRA
serverIdeee25142-2510-336f-918a-865682ebdf2e
keyCIT-127