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Gene function

The ATM gene encodes for the multifunctional protein ATM, which participates in different overlapping processes involved in the maintenance of genomic stability.

ATM is one of a number of phosphatidylinositol-3 kinase (PIK3)-like serine/threonine kinases, another being ATR. ATM is activated by double-stranded DNA damage (for example, by ionising radiation), while ATR is activated by lesions leading to the formation of single-stranded DNA (for example, during double-stranded break processing or replication stress). Activation of ATM and ATR leads to the initiation of homologous recombination repair, the major pathway for the repair of double-stranded DNA breaks.

Gene locus and structure

The ATM gene is located at chromosome 11q22.3. It is a large gene, containing 63 exons (62 coding; exon 1 is non-coding).


The population frequency of likely pathogenic and pathogenic variants in ATM is relatively high, with an estimated worldwide population frequency of 1 in 100 (1%).

Pathogenic variant spectrum

  • The majority of variants in ATM are sequence variants involving single nucleotides, but larger deletions and duplications have been reported.
  • The cancer risks associated with pathogenic ATM variants are variant-specific, with truncating variants associated with higher risks than missense variants (apart from the recurrent missense variant c.7271T>G (p.Val2424Gly), which confers a higher risk of breast cancer than other ATM variants).

Disease associations

Somatic (tumour) variants in ATM

  • Somatic (tumour) variants in ATM are common across a host of cancers, including colorectal, prostate and lung cancers. Precision treatment options, such as PARP inhibitors, may be available for patients affected with ATM-deficient cancers. Specific ATR inhibitors are currently under investigation in clinical and pre-clinical trials.

Hereditary cancer risk

  • Constitutional (germline) monoallelic (heterozygous) pathogenic variants in ATM are associated with an increased risk of breast cancer, pancreatic cancer, prostate cancer, and possibly other cancers.
  • Much of the available data has allowed calculation of odds ratios (OR) of cancer, rather than cumulative lifetime (CL) risks. Estimated cancer risks for individuals with pathogenic constitutional (germline) variants in ATM are genotype-specific. Some are outlined in table 1.

Table 1: Estimated cancer risks for individuals with constitutional (germline) ATM variants

Cancer Population risk ATM c.7271T>G (p.Val2424Gly) ATM truncating variants Other ATM missense variants
Female breast cancer* 12% OR 3.76 (2.76–5.21)

CL risk: 52% (28–80)

OR 2.10 (1.71–2.57) OR 1.06 (1.00–1.13)
Male breast cancer* 0.1% OR 8.31 (95% confidence interval 1.46–47.27) OR: 1.72 (1.08–2.75) OR: 1.72 (1.08–2.75)
Pancreatic cancer 1.5% OR 4.21 (3.24–5.47)

Reported CL risk: 9.5% (5.04–14.02)

OR 4.21 (3.24–5.47)

Reported CL risk: 9.5% (5.04–14.02)

OR 4.21 (3.24–5.47)

Reported CL risk: 9.5% (5.04–14.02)

Ovarian cancer 2% OR 1.57 (1.35–1.83) OR 1.57 (1.35–1.83) OR 1.57 (1.35–1.83)
Prostate cancer 12% OR 2.58 (1.93–3.44) OR 2.58 (1.93–3.44) OR 2.58 (1.93–3.44)

* Breast cancer risks for trans people who use cross-sex hormones are currently uncertain, but may be lower than those typically seen in women and higher than those typically seen in men.


  • There is some evidence to suggest that ATM-associated breast tumours are more likely to be oestrogen receptor (ER)-positive.
  • Robust genotype-specific risk estimates for non-breast cancers are not yet available.
  • The risk of second primary breast cancers in individuals with likely pathogenic or pathogenic variants in ATM is uncertain, but there is some evidence to suggest it is increased.

Recessive conditions associated with pathogenic variants in ATM

  • Individuals who have pathogenic variants in both copies of their ATM gene (biallelic variants – both homozygous or compound heterozygous) are affected by a condition known as ataxia telangiectasia, a progressive neurological condition characterised by early-onset cerebellar ataxia, choreoathetosis, conjunctival telangiectasia, immunodeficiency and recurrent infections, increased predisposition and radiosensitivity.
  • Individuals with monoallelic (heterozygous) constitutional (germline) pathogenic variants in ATM are not at risk of ataxia telangiectasia but do have an increased cancer risk, predominantly of breast, prostate and pancreatic cancer.

Genomic testing

  • The clinical phenotype associated with pathogenic and likely pathogenic variants in ATM may be clinically indistinguishable from that associated with likely pathogenic and pathogenic variants in BRCA1, BRCA2, PALB2, RAD51C, RAD51D or CHEK2. For this reason, testing of all these genes is typically undertaken simultaneously as part of a small panel for eligible patients.
  • Constitutional (germline) genomic testing of ATM is available through the National Genomic Test Directory for individuals affected by breast, ovarian, prostate or pancreatic cancer who meet the eligibility criteria. At present, laboratories in the NHS do not report missense variants (other than ATM c.7271T>G) given the relative lack of robust penetrance estimates associated with this class of variant, and given the challenges in interpretation of missense variation.
  • ATM is also included in the gene panel test for eligible patients with features suggestive of ataxia telangiectasia. The test may be ordered by clinicians in the relevant specialties as appropriate. The test directory indications are:
    • R15 Primary immunodeficiency;
    • R326 Vascular skin disorders;
    • R54 Hereditary ataxia – adult onset;
    • R55 Hereditary ataxia – childhood onset;
    • R56 Adult onset movement disorder;
    • R57 Childhood onset dystonia or chorea, or related movement disorder; and
    • R359 Childhood tumour predisposition.
  • Site-specific ATM testing may be available under indication R240 (Diagnostic testing for known mutation), in the following scenarios:
    • for parents and other at-risk relatives of individuals affected by ataxia telangiectasia, where the molecular diagnosis has been confirmed, for the purpose of identifying cases in the family and to provide individuals with heterozygous variants with information about family planning implications (such testing is co-ordinated by clinical genetics services); and
    • for individuals with a cancer in which a pathogenic ATM variant that may be of constitutional (germline) origin has been identified during somatic (tumour-based) testing, where paired germline testing has not been undertaken.
  • Note that in both scenarios described above, it is important to confirm with the laboratory whether confirmatory testing will be offered, depending on the variant type in question and potential implications for individuals in the case of a positive result.

Genomic counselling

  • The cancer risk associated with constitutional (germline) ATM variants is inherited in an autosomal dominant pattern. Ataxia telangiectasia is inherited in an autosomal recessive pattern.
  • First-degree relatives of an individual with a likely pathogenic or pathogenic variant in ATM have a 50% chance of having the familial variant. Affected individuals should be referred to clinical genetics services for genetic counselling and cascade screening.

Risk-reducing strategies

Risk-reducing strategies offered to individuals with likely pathogenic or pathogenic variants in ATM are dependent on the genotype and family history.

In the absence of formal national guidelines, proposed management of risk in such patients is outlined below.

Breast cancer risk management

Symptom awareness

  • All affected individuals should be provided with advice regarding symptom awareness.


  • Individuals with the high-risk missense variant c.7271T>G (p.Val2424Gly) are eligible for BRCA-equivalent screening through the NHS’s very high-risk breast cancer screening programme.
  • Individuals with confirmed ataxia telangiectasia are also eligible for very high-risk breast screening from 25 years of age, with an annual MRI (mammogram is best avoided in such individuals, given the associated radiosensitivity and increased risk of radiation-induced cancer).
  • Individuals with truncating variants in ATM should be offered at least moderate-risk breast screening (annual mammograms between 40 and 50 years of age, followed by population screening) but may be offered high-risk breast screening (annual mammograms between 40 and 60 years of age, followed by population screening) if the estimated lifetime risk of breast cancer, determined by family history and CanRisk estimation, is 30% or higher.
  • If an individual has had a missense variant in ATM identified (for example, through private or self-funded testing or cascade testing in relatives of individuals with ataxia telangiectasia), screening should be individualised and guided by family history rather than genotype. Caution should be exercised in using CanRisk to determine screening in individuals with variants of lower penetrance, given that genotype-specific calculations are not possible at present.

Breast cancer management considerations

  • Individuals with ataxia telangiectasia are extremely susceptible to radiation-related toxicity. For this reason, radiation (therapeutic and diagnostic) should be avoided where a non-inferior alternative treatment exists. There are some data suggesting that there may be an increased risk of radiation-induced second primary cancers in people with rare missense variants, but further work and larger studies are required to clarify risk. At present, treatment of breast cancer in those with heterozygous ATM variants is as per standard practice.

Risk-reducing breast surgery

  • The role of risk-reducing bilateral mastectomy in individuals with likely pathogenic or pathogenic ATM variants is uncertain, but it may be considered for those with higher-risk variants and an estimated lifetime breast cancer risk of 30% or higher.
  • The survival advantage of surgery compared with surveillance is uncertain.
  • Contralateral prophylactic mastectomy in an individual with a higher-risk ATM variant who has already been affected by breast cancer may be considered and, if feasible, may be undertaken at the same time as therapeutic mastectomy.
    • Contralateral prophylactic surgery will minimise the risk of a second primary breast cancer, but the risk of recurrence from the first breast cancer should be carefully considered when counselling the patient about the potential advantages of this surgery.
    • It is best practice for decisions regarding prophylactic surgery in such individuals to be made only after discussion at a specialist multidisciplinary team meeting, with input from clinical genetics.


  • Guidance from NICE published in March 2017 recommends that chemoprevention with tamoxifen, raloxifene or anastrozole should be considered in women at increased risk of breast cancer based on their family history, after giving due consideration to potential contraindications and risks of adverse events.
  • The role of chemoprophylaxis in the prevention of ATM-associated breast cancer has not been specifically explored.

Male breast cancer risk management

  • Breast cancer screening is not recommended in men with pathogenic ATM variants, but breast symptom awareness is encouraged, particularly for those with the high-risk c.7271T>G (p.Val2424Gly) variant.

Pancreatic cancer risk management

  • As screening has not yet been proven to impact mortality from pancreatic cancer, the consensus from the UK Cancer Genetics Group is that screening for this type of cancer should not be offered outside of research studies at present.
  • Patients should be counselled regarding modifiable risk factors (including smoking) and symptom awareness.

Prostate cancer risk management

  • The role of prostate cancer screening with prostate-specific antigen and MRI in individuals with ATM pathogenic or likely pathogenic variants is uncertain and is an area of active research.
  • Men with such variants should be counselled regarding symptom awareness.

Other cancers

  • At present, screening for other cancer types is not typically recommended, unless otherwise required because of a strong family history.

Referral to clinical genetics

  • Referral of affected patients to clinical genetics should be arranged to discuss onward management, family planning implications and cascade testing of at-risk relatives. Testing of spouses or partners may be considered where there is a significant risk that a child may be affected by ataxia telangiectasia (for example, if the parents are in a consanguineous relationship).

Family planning implications

  • The Human Fertilisation and Embryology Authority has approved the use of preimplantation genetic testing for monogenic disorders (PGT-M – previously known as preimplantation genetic diagnosis) for couples in whom both intended parents have a likely pathogenic or pathogenic variant in ATM, meaning that there is a risk of them having a child affected by ataxia telangiectasia.
  • PGT-M is also licensed for couples in whom one of the intended parents has the high-risk c.7271T>G (p.Val2424Gly) variant.
  • PGT-M may be considered if one of the intended parents has another pathogenic variant in ATM, if an HFEA licence application is possible and approved.
  • Other options for family planning may include prenatal testing with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.
  • Discussions regarding PGT-M and other family planning options should be undertaken by a specialist genetic counsellor or clinical geneticist.


For clinicians


For patients

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  • Last reviewed: 11/06/2023
  • Next review due: 11/06/2025
  • Authors: Dr Terri McVeigh
  • Reviewers: Dr Ellen Copson