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ATM

Alias

AT1; ATA; ATC; ATD; ATDC; ATE; TEL1; TELO1

Associated disorders

The ATM gene is associated with an increased risk for autosomal dominant breast and pancreatic cancer (PMID: 15928302, 15942625, 16998505, 22585167, 26483394, 26662178). There is also preliminary evidence supporting a correlation with autosomal dominant colorectal, prostate, and possibly other cancers (PMID: 15928302, 15942625, 26662178). Additionally, the ATM gene is associated with autosomal recessive ataxia-telangiectasia (A-T) (MedGen UID: 439).

The gene ATM (ataxia telangiectasia mutated) encodes a protein that is an important cell cycle checkpoint kinase that phosphorylates. It functions as a regulator of a wide variety of downstream proteins, including tumor-suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways required for cell response to DNA damage and for genome stability.

ATM heterozygote
MedGen UID: 87542

Clinical condition
Women who are carriers of a single pathogenic ATM variant have an increased risk of breast cancer that ranges between 17–60% risk of breast cancer (PMID: 11830610, 16832357, 15928302, 16998505, 3574400, 16832357, 15880680, 16958054, 1961222, 21787400, 26662178, 27595995). Men with a single pathogenic variant in ATM have an increased risk of prostate cancer (PMID: 27433846, 18565893, 15280931, 17502119, 24556621), and both men and women have an increased risk of pancreatic cancer, although specific risks estimates are not yet established (PMID: 22585167, 26098866, 26483394). There may also be risks for other cancer types, however the current evidence is limited and emerging (PMID: 25622547, 15928302, 18565893, 21396839).

There is also evidence to suggest an association between ATM and colorectal cancer, and is therefore available as a “preliminary-evidence” gene on the Invitae Colorectal Cancer Syndrome Panel (PMID: 15928302, 15942625). Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not yet been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes. There may also be risks for other cancer types among individuals with a single pathogenic ATM variant, however the current evidence is limited and emerging (PMID: 25622547, 15928302, 18565893, 21396839).

Gene information
The protein encoded by the ATM gene belongs to the PI3/PI4-kinase family. This protein is an important cell-cycle checkpoint kinase that phosphorylates. It functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint-signaling pathways that are required for cell response to DNA damage and for genome stability (NCBI Gene. Gene ID: 472. http://www.ncbi.nlm.nih.gov/gene/472. Accessed January 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain cancers may be increased.

Inheritance
Hereditary predisposition to cancer due to pathogenic variants in the ATM gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant who has parents who do not have it).

Individuals with a single pathogenic variant in ATM are also carriers of ataxia-telangiectasia (A-T). A-T is an autosomal recessive condition that results when an individual inherits a pathogenic ATM variant from each parent. Features include progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, premature aging, endocrine abnormalities, and increased risk for malignancy—particularly leukemia and lymphoma (PMID: 20301790, 15279807, 26050521). For there to be a risk of A-T in offspring, both the patient and his/her partner would each have to carry a pathogenic variant in ATM. In this case, the risk of having have an affected child would be 25%.

Medical management guidelines and surveillance recommendations
The National Comprehensive Cancer Network® (NCCN®) has published screening and surveillance guidelines for women with a single pathogenic variant in ATM (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017 accessed January 10, 2017):

  • annual mammography starting at age 40 years
  • consider annual breast MRI with contrast starting at age 40, with modification as appropriate based on family history or specific gene mutation
  • annual mammography beginning at age 40, with modification as appropriate based on family history or specific gene mutation
  • consider annual breast MRI with contrast starting at age 40, with modification as appropriate based on family history or specific gene mutation
  • consider risk-reducing mastectomy based on family history
  • referral to genetic counseling inclusive of a discussion regarding recurrence risks for both autosomal dominant and autosomal recessive ATM-related conditions

There has been some debate as to whether ionizing radiation is considered significantly carcinogenic to individuals with a single pathogenic ATM variant. There is currently no substantial evidence to suggest there are additional side effects from ionizing radiation compared to those who do not have an ATM pathogenic variant (PMID: 26662178, NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2017).
NCCN® cites insufficient evidence to warrant screening for prostate and pancreatic cancer (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017, accessed January 10, 2017). In contrast, the American College of Gastroenterology Clinical Guidelines recommend pancreatic cancer screening for individuals with a single pathogenic ATM variant be limited to those with a first- or second-degree relative affected with pancreatic cancer. Ideally, screening should be performed in experienced centers utilizing a multidisciplinary approach under research conditions. Recommended screening includes annual endoscopic ultrasound and/or MRI of the pancreas starting at age 50 or 10 years younger than the earliest age of pancreatic cancer diagnosis in the family (PMID: 25645574).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic ATM variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding this gene are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow recommended screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: January 2017

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2017. © National Comprehensive Cancer Network, Inc 2016. All rights
reserved. Accessed 9/26/16. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ATM NM_000051.3