GTS5:Ataxia-telangiectasia syndrome (ATM)

Genetic Tumour Syndromes (Who Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Emilie Lalonde, MSc, PhD, FACMG

WHO Classification of Disease

Structure	Disease
Book	Genetic Tumour Syndromes (5th ed.)
Category	DNA repair and genomic stability
Family	Non-homologous end joining (NHEJ)
Type	Ataxia-telangiectasia syndrome (ATM)
Subtype(s)	N/A

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Other: Boder-Sedgwick syndrome

Definition/Description of Disease

- The ATM gene is located on 11q22.3 and contains 66 exons. It encodes the ATM protein, an important kinase which is a key regulator of DNA damage repair and cell cycle control pathways, among others. ATM is recruited to double strand breaks, and upon activation, phosphorylates other signaling proteins involved in DNA repair, cell cycle checkpoints and apoptosis. ATM is a tumor suppressor and pathogenic variants result in reduced DNA damage response.

- Heterozygous pathogenic germline variants are associated with autosomal dominant ATM-related cancer predisposition, which increases susceptibility to a range of hereditary cancers, most notably breast, prostate and pancreatic cancers. ATM is considered a moderate penetrance cancer predisposition gene, with a 2-3 fold increase in breast cancer risk compared to the general population with an absolute risk of 21-24%. ATM has also been associated with predisposition to ovarian cancer, colorectal cancer and melanoma, but additional confirmatory studies are needed.

- Biallelic pathogenic germline variants are associated with autosomal recessive ataxia telangiectasia (AT), a rare multisystem neurodegenerative disorder. Individuals with AT are at significantly increased risk of lymphoid malignancies in childhood or early adulthood as well as early-onset breast cancer. Individuals with AT have significant radiosensitivity and should not be treated with radiation therapy.

(Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.)

Epidemiology/Prevalence

- The incidence of heterozygous pathogenic germline variants is estimated to range from approximately 1:100 to 1:400, depending on the population.

Genetic Abnormalities: Germline

Variant nomenclature is based on the NM_000051.4 transcript. (Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
ATM	SNVs (frameshift, nonsense, missense, splice site, synonymous, splice); CNVs (inactivating deletions or duplications)	Multiple variant types leading to loss of function	Autosomal dominant, moderate penetrance for carriers. Autosomal recessive, Fanconi anemia (FA) subtype N, 100% penetrance.	Loss of function is the mechanism for both diseases; the same pathogenic variant in the heterozygous state would be associated with AT in the homozygous state, and vice versa. Some individuals with AT may have some retained kinase activity, rather than complete loss. This is most commonly associated with splice site or missense variants, and are associated with lower penetrance and "variant" AT (less severe, later onset, etc.). There are some higher penetrant pathogenic variants, such as c.7271T>G p.(Val2424Gly) and c.7570G>C p.(Ala2524Pro), associated with a 4-6 fold increase in breast cancer. Founder mutations: - c.5763-1050A>G (British ancestry) - c.103C>T, p.(Arg35*) (Moroccan & Tunisian Jewish ancestry) - c.1339C>T, p.(Arg447*) (northern Israel Druze population originally from central Lebanon & Jordan) - c.1564_1565delAG, p.(Glu522Ilefs*43) (Amish ancestry) - c.4507C>T, p.(Gln1503*) (Costa Rican population) - c.5908C>T, p.(Gln1970*) (Costa Rican population) - c.6200C>A, p.(Ala2067Asp) (Canadian Mennonite population) - c.6672_6680delGGCTCTACGinsCTC, p.(Met2224_Arg2227delinsIleSer) (northern Israel Druze population originally from central Lebanon & Jordan) - c.7449G>A, p.(Trp2483*) (Costa Rican population) - c.9007_9034del28, p.(Asn3003Aspfs*6) (Romani population in Spain)

Genetic Abnormalities: Somatic

Put your text here and fill in the table (Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
ATM	Biallelic inactivation variants	Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

For cancer predisposition, a multi-gene next-generation sequencing (NGS) panel is recommended, either a comprehensive cancer predisposition panel or a smaller gene panel tailored to the personal and family cancer history.

For AT, depending on the phenotype and differential diagnosis, either single gene or multi-gene NGS testing is recommended. Chromosome instability studies may also help clarify a diagnosis in case of inconclusive molecular testing.

For individuals of British ancestry, the intronic founder mutation, c.5763-1050A>G, should be included in testing. This variant may be missed by exome sequencing, depending on panel design. Review of laboratory methodology is recommended prior to testing.

(Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

Additional Information

- According to ACMG clinical management guidelines, management of individuals with heterozygous germline pathogenic variants should be based on an individualized risk assessment model, including personal and family history, rather than on the presence of anATM variant alone. These individuals may qualify for enhanced breast cancer surveillance, earlier screening for prostate and pancreatic cancers, depending on country-specific criteria. In general, risk-reducing mastectomy and risk-reducing salpingo-oophorectomy are not routinely recommended, but may be considered/discussed based on individualized risk assessment.

- While ionizing and radiation therapy is contraindicated in individuals with biallelic germline pathogenic variants (i.e. diagnosed with AT), they are considered safe for heterozygous carriers.

- Due to reduced DNA damage response in individuals with biallelic variants in their tumors (germline and/or somatic), PARP inhibitors have been explored for therapeutic treatment in patients with various cancers. At this time, there is limited evidence supporting the use of PARP inhibitors in patients with ATM variants. However, some PARP inhibitors are approved for use on any tumor with a HRR gene mutation, including ATM.

Links

Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):