GTS5:Ataxia-telangiectasia syndrome (ATM): Difference between revisions

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 <span style="color:#0070C0">(''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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
 ==Primary Author(s)*==
-Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
+Emilie Lalonde, MSc, PhD, FACMG
 ==WHO Classification of Disease==
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 ==Definition/Description of Disease==
-Put your text here <span style="color:#0070C0">(''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.'')</span>
+- 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<ref>{{Cite journal|last=Phan|first=Liem Minh|last2=Rezaeian|first2=Abdol-Hossein|date=2021-05-30|title=ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development|url=https://www.mdpi.com/2073-4425/12/6/845|journal=Genes|language=en|volume=12|issue=6|pages=845|doi=10.3390/genes12060845|issn=2073-4425|pmc=8228802|pmid=34070860}}</ref><ref name=":2">{{Cite journal|last=Lee|first=Ji-Hoon|last2=Paull|first2=Tanya T.|date=2021-12|title=Cellular functions of the protein kinase ATM and their relevance to human disease|url=https://www.nature.com/articles/s41580-021-00394-2|journal=Nature Reviews Molecular Cell Biology|language=en|volume=22|issue=12|pages=796–814|doi=10.1038/s41580-021-00394-2|issn=1471-0072}}</ref>. 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<ref name=":2" />.
+- 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<ref name=":0" /><ref name=":1" />. 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%<ref name=":0">{{Cite journal|last=Pal|first=Tuya|last2=Schon|first2=Katherine R.|last3=Astiazaran-Symonds|first3=Esteban|last4=Balmaña|first4=Judith|last5=Foulkes|first5=William D.|last6=James|first6=Paul|last7=Klugman|first7=Susan|last8=Livinski|first8=Alicia A.|last9=Mak|first9=Julie S.|date=2025-01|title=Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)|url=https://linkinghub.elsevier.com/retrieve/pii/S1098360024001771|journal=Genetics in Medicine|language=en|volume=27|issue=1|pages=101243|doi=10.1016/j.gim.2024.101243}}</ref><ref name=":1">NCCN Guidelines Version 3.2025, Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.</ref>. 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<ref name=":2" />. Individuals with AT are at significantly increased risk of lymphoid malignancies in childhood or early adulthood as well as early-onset breast cancer<ref name=":0" />. Individuals with AT have significant radiosensitivity and should not be treated with radiation therapy.
+<span style="color:#0070C0">(''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.'')</span>
 ==Epidemiology/Prevalence==
-Put your text here
+- The incidence of heterozygous pathogenic germline variants is estimated to range from approximately 1:100 to 1:400, depending on the population<ref name=":0" />.
 ==Genetic Abnormalities: Germline==
-Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
+Variant nomenclature is based on the NM_000051.4 transcript. <span style="color:#0070C0">(''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.'')</span>
 {| class="wikitable sortable"
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 !Notes
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-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Many||<span class="blue-text">EXAMPLE:</span> Multiple variant types leading to loss of function||<span class="blue-text">EXAMPLE:</span> Autosomal recessive,
+|''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.
-~30% penetrant 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<ref>{{Cite journal|last=Richardson|first=Marcy E.|last2=Holdren|first2=Megan|last3=Brannan|first3=Terra|last4=de la Hoya|first4=Miguel|last5=Spurdle|first5=Amanda B.|last6=Tavtigian|first6=Sean V.|last7=Young|first7=Colin C.|last8=Zec|first8=Lauren|last9=Hiraki|first9=Susan|date=2024-11|title=Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants|url=https://linkinghub.elsevier.com/retrieve/pii/S000292972400332X|journal=The American Journal of Human Genetics|language=en|volume=111|issue=11|pages=2411–2426|doi=10.1016/j.ajhg.2024.08.022|pmc=11568761|pmid=39317201}}</ref>.
+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.'')<ref name=":0" />.
+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<ref name=":0" />.
+Founder mutations<ref>Veenhuis S, van Os N, Weemaes C, et al. Ataxia-Telangiectasia. 1999 Mar 19 [Updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26468/.</ref>:
+- 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)
+|-
+|
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-|-
-|<span class="blue-text">EXAMPLE:</span> Gene X
-|<span class="blue-text">EXAMPLE:</span> List the specific mutation
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 !Notes
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-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants||<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||
+|''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.||
 |
 |-
-|<span class="blue-text">EXAMPLE:</span> ''BRCA1''
+|
-|<span class="blue-text">EXAMPLE:</span> Reversion mutation
+|
-|<span class="blue-text">EXAMPLE:</span> After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.
+|
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 |}
 ==Genetic Diagnostic Testing Methods==
-Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
+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.
+<span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
 ==Additional Information==
-Put your text here
+- 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<ref name=":0" />. 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<ref name=":0" />.
+- 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<ref name=":0" />. 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 <span style="color:#0070C0">(''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 "<nowiki>http://www</nowiki>." portion.'')</span>
 ==References==
+<references />
 (use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
 ==Notes==