ATM (monoallelic pathogenic variants) – risk management

Familial cancer predisposition due to a germline pathogenic variant in the ATM gene is an autosomal dominant condition. ATM c.7271T>G is associated with a high risk of breast cancer that is similar to that associated with a germline BRCA2 pathogenic variant.^rr Other monoallelic pathogenic variants in ATM are reported to be associated with a moderately increased risk of breast cancer (two-to threefold increased risk).^rrr In those who carry monoallelic pathogenic variants in ATM (excluding ATM c.7271T>G), lifetime breast cancer risk may be influenced by additional personal risk factors, family history and polygenic risk. Consequently, in some individuals with ATM variants, breast cancer risk may approach population risk.

Monoallelic ATM pathogenic variants are also associated with an increased risk of other cancers including pancreatic and prostate cancer.

Biallelic ATM pathogenic variants result in ataxia-telangiectasia (AT), which is an autosomal recessive disease resulting in severe neurodegeneration, immunodeficiency and increased risk of cancer. Counsel ATM pathogenic variant carriers on the risk of AT in offspring - see Facts for people from a family with a faulty ATM gene who are planning a pregnancy.

• Known or obligate ATM pathogenic variant carrier with no personal history of cancer
• Individual at 50% risk of being an ATM pathogenic variant carrier

Exclusion criteria

• ATM pathogenic variant carriers with a personal history of breast, pancreatic or prostate cancer
• Individuals with a pathogenic variant in another breast cancer predisposition gene 
• High risk breast cancer family where no gene fault was identified or no DNA testing available
• High risk breast and ovarian cancer family where no gene fault was identified or no DNA testing available
• Individuals with an ATM variant of uncertain significance

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional. Some ATM carriers with no family history of cancer may be close to population risk. Additionally, it is important to note that the risk prediction tool CanRisk opens in a new tab or window has only been validated for truncating ATM variants. CanRisk also has the potential to underestimate the risk associated with the ATM c.7271T>G pathogenic variant, and as such is not recommended in this scenario. 

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure. Decisions about hormonal contraception should weigh a possible increase in breast cancer risk against the benefits. See Management of associated health issues below for additional information.

Cancer/tumour type	Recommendations
Breast (female)		Strategy and frequency
		Moderate lifetime risk individuals^ (Other ATM pathogenic variant carriers excluding c.7271T>G)	High lifetime risk individuals^ (Other ATM pathogenic variant carriers excluding c.7271T>G)	High lifetime risk individuals^ (ATM c.7271T>G pathogenic variant carriers)
	Surgical	Risk reducing mastectomy is not recommended for ATM pathogenic variant carriers assessed as having a moderate lifetime risk of breast cancer	Consider bilateral risk-reducing mastectomy for ATM pathogenic variant carriers assessed as having a high lifetime risk of breast cancer  The appropriateness and optimal timing should be individualised based on patient preference and risk trajectory	Consider bilateral risk-reducing mastectomy for ATM c.7271T>G pathogenic variant carriers The appropriateness and optimal timing should be individualised based on patient preference and risk trajectory
	Surveillance All ages	Breast awareness with prompt reporting to GP of persistent or unusual changes	Breast awareness with prompt reporting to GP of persistent or unusual changes	Breast awareness with prompt reporting to GP of persistent or unusual changes
	Surveillance Age 30-40 years	No routine screening recommended	Assess 10-year breast cancer risk using a validated risk model such as CanRisk opens in a new tab or window^ Annual breast MRI# if screening is advised	Recommend annual breast MRI# (US if MRI not possible) In families with breast cancer diagnosed under age 35 years individualised screening recommendations may apply. Otherwise screening should start at age 30 years
	Surveillance Age 40-50 years	Recommend annual MMG Assess 10-year breast cancer risk using a validated risk model such as CanRisk opens in a new tab or window Consider annual breast MRI# if 10-year risk is >5%	Recommend annual breast MRI# + annual MMG (MMG + US if MRI not possible)	Recommend annual breast MRI# + annual MMG (MMG + US if MRI not possible)
	Surveillance Age 50-60 years	Recommend MMG every second year Consider annual MMG or MRI if concerning features e.g. dense breast tissue	Recommend annual breast MRI# + annual MMG (MMG + US if MRI not possible)	Recommend annual breast MRI# + annual MMG (MMG + US if MRI not possible)
	Surveillance Over age 60 years	Recommend MMG every second year Consider other imaging modalities depending on individual risk factors e.g dense breast tissue	Recommend annual MMG Consider annual breast MRI if over age 60 years with dense breast tissue (US if MRI not possible)	Recommend annual MMG Consider annual breast MRI if over age 60 years with dense breast tissue (US if MRI not possible)
	Surveillance in pregnancy	No MRI or MMG, consider US or CBE
	Risk-reducing medication	Consider use of medication to reduce risk of developing breast cancer for women not planning bilateral mastectomy within 3 years: Pre-menopausal women may consider tamoxifen Post-menopausal women may consider raloxifene, aromatase inhibitors or tamoxifen See COSA – Medications to lower the risk of breast cancer: clinician guide opens in a new tab or window and offer COSA – Medications to lower the risk of breast cancer: patient guide opens in a new tab or window
Pancreatic	Surveillance	For all ATM pathogenic variant carriers There is emerging but limited evidence of survival benefit from surveillance Where possible surveillance should be carried out as part of a clinical trial^^ Consider annual surveillance with endoscopic US or contrast enhanced MRI/MRCP from age 50 years (or 5-10 years younger than the affected relative) in ATM pathogenic variant carriers with at least one first- or second-degree relative with exocrine pancreatic cancerr Avoid smoking and obesity and minimise alcohol consumption
Prostate	Surveillance	For all ATM pathogenic variant carriers No evidence of benefit from surveillance

Abbreviations: MRI – magnetic resonance imaging, US – ultrasound, MMG – mammogram (digital, consider tomosynthesis where possible), CBE – clinical breast examination, MRCP - magnetic resonance cholangiopancreatography.
^ Risk modelling with CanRisk opens in a new tab or window is only validated with truncating ATM variants. Lifetime risk is calculated from age 20-80 years.
# Refer to MBS Item 63464 opens in a new tab or window for specific criteria for MBS funding of MRI.
^^ Refer to Australian Pancreatic Cancer Genome Initiative opens in a new tab or window for up-to-date screening trials. 

Breast cancer (all ATM pathogenic variant carriers)

Breast cancer risk should be formally assessed using a validated risk prediction tool such as CanRisk opens in a new tab or window. These tools can be used to estimate 5- and 10-year breast cancer risks for women with a family history of breast cancer and can help personalise screening recommendations for ATM pathogenic variant carriers. Additionally, it is important to note that the risk prediction tool CanRisk has only been validated for truncating ATM variants. CanRisk thus has a potential to underestimate the risk associated with the ATM c.7271T>G pathogenic variant, and as such is not recommended in this scenario.

Surgical

Risk-reducing mastectomy is not recommended for women at moderate lifetime risk of breast cancer. Consider risk-reducing mastectomy for ATM pathogenic variant carriers assessed as high lifetime risk of breast cancer.

Surveillance

Breast screening is generally recommended when the 5-year risk exceeds the 5-year risk for a woman at age 50 years (i.e. 5 year risk greater than 1%), when population screening with mammography commences.^r This occurs at age 40 years for women with ATM gene pathogenic variants and no strong family history.^r Annual mammography is both cost effective and clinically effective in reducing breast cancer predicted mortality.^r

Surveillance plans should be individualised for women with ATM pathogenic variants where a validated risk prediction tool (CanRisk) places them at high lifetime risk and should include annual magnetic resonance imaging (MRI) or mammogram (MMG).

Risk reducing medication

Selective oestrogen receptor modulators (SERM), such as tamoxifen and raloxifene, have been shown to reduce the risk of oestrogen receptor-positive breast cancer in women identified to be at increased risk. Pathogenic variants in ATM are associated with an increased risk of ER positive breast cancer.^rr In a meta-analysis, SERM reduced breast cancer incidence by 38% (HR 0.62; 95% CI, 0.56–0.69) compared with placebo in women at increased risk with the risk reduction extending beyond the treatment period.^r

To date studies have not included enough ATM pathogenic variant carriers to determine if it is effective for primary prevention in this population.

As with all interventions, discussion of risks and benefits should occur. See COSA – Medications to lower the risk of breast cancer: clinician guide. opens in a new tab or window

Additional breast cancer management (ATM c.7271T>G carriers only)  

At the present time, and while there is no specific evidence related to ATM (c.7271T>G) pathogenic variant carriers, these guidelines are based on those that apply to the management of breast cancer risk in female BRCA2 pathogenic variant carriers

Surgical

Consider bilateral risk-reducing mastectomy for ATM c.7271T>G pathogenic variant carriers. Bilateral risk reducing mastectomy reduces breast cancer risk by at least 90% (depending on the operation performed) in BRCA1 or BRCA2 pathogenic variant carriers.^r Statistically significant survival benefit associated with bilateral risk-reducing mastectomy compared with surveillance is yet to be demonstrated.

Surveillance

Magnetic resonance imaging (MRI) is the preferred screening technique due to its high sensitivity compared with mammogram (MMG) or ultrasound (US). The addition of MMG is limited and does not lead to a significant increase in sensitivity compared with MRI alone.^r There is no added value of US or clinical breast exam in women undergoing MRI for screening.^r MRI detects tumours which are smaller and more likely to be node-negative than MMG. MRI has a recall rate (requiring further investigation and/or biopsy) of 15% for initial screening, which decreases with subsequent rounds of screening to <10%.

Pancreatic cancer (all ATM pathogenic variant carriers)

One recently published screening study of patients at high risk of developing pancreatic cancer (including patients with ATM pathogenic variants and a family history of pancreatic cancer) found that most screen-detected pancreatic cancers were stage I with favourable long-term outcomes compared with unscreened populations.^r

If surveillance is offered it should be undertaken in an experienced high-volume centre after detailed discussion regarding limitations of screening including cost, high incidence of benign or indeterminate pancreatic abnormalities and uncertainties about the benefit. Most small cystic lesions found on screening will not warrant biopsy, surgical resection, or any other intervention.

Prostate cancer (all ATM pathogenic variant carriers)

There is currently no evidence of efficacy of prostate cancer screening in ATM pathogenic variant carriers.

Radiation therapy (all ATM pathogenic variant carriers)

There are mixed reports regarding the effects of radiation on heterozygous ATM pathogenic variant carriers. However, radiation therapy at conventional doses is not contraindicated in ATM pathogenic variant heterozygous carriers and should be considered and delivered if required clinically.^rr

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or a familial cancer centre opens in a new tab or window to discuss predictive genetic testing.

Counsel ATM pathogenic variant carriers on the risk of autosomal recessive disorder ataxia-telangiectasia (AT) in offspring. See Facts for people from a family with a faulty ATM gene who are planning a pregnancy.

Informing family members about hereditary cancer.

Research Studies

Research is taking place in all aspects of hereditary breast and ovarian cancer. Families may be invited to participate in research trials. Speak to your doctor for more information.

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Version 10

Date	Summary of changes
28/11/2024	Protocol reviewed at March 2024 cancer genetics reference committee meeting. Discussions continued via MS Teams and email. All sections of protocol revised. Refer to PDF of previous version to compare changes. Version increased to V.10. Approved on 17/10/2024, published on 28/11/2024. Review in 2 years.

Version 9

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.9.

Version 8

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: Template sentence updated. Target population: Added to exclusion criteria "Individual with a variant of uncertain significance". Cancer/tumour risk management guidelines: Template sentence updated. Lifestyle factors sentence moved above the table. Management of associated health problems: Accordion title changed to "Management of associated health issues" Subheading "Contraception and fertility" changed to "Contraception". Version number increased to V.8.

Version 7

Date

Summary of changes

05/05/2022

Protocol discussed at May 2021 cancer genetics reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made:  Title: '(monoallelic c.7271T>G)' changed to '(monoallelic pathogenc variants)' and removed '(female)' from title as protocol now applicable males and females Summary: first two paragraphs completely re-written Target group: 'c.7271T>G' and 'female' removed target population Lifetime risk of cancer/tumour: Breast cancer - All other ATM pathogenic variants: added to table Prostate cancer: added to table Pancreatic cancer: 'May be increased' changed to 'Increased but not well quantified General population risk updated to AIHW 2017 data Cancer/tumour risk management guidelines Separate sections created for 'ATM c.7271T>G' and 'All other ATM pathogenic variants (excluding c.7271T>G)' Prostate cancer added to both tables Management of associated health problems: section added Evidence for risk management guidelines Separate sections created for 'ATM c.7271T>G' and 'All other ATM pathogenic variants (excluding c.7271T>G)' Breast and pancreatic sections reviewed and updated Prostate cancer subsection added Radiation therapy subsection added Version number increased to V.7. Review in 2 years.

Version 6

Date	Summary of changes
27/11/2019	"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs Definition of "pathogenic variant" added as a pop-up Lifetime risk of cancer - Breast cancer - Risk for ATM (c.7271T>G) pathogenic variant carrier up to age 70 years - reference changed to Bernstein et al 2006 Version number increased to V.6.
18/12/2020	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Related pages: link to "Cancer predisposition genes: population carrier frequency" added Lifetime risk of cancer table: Heading changed to "Lifetime risk of cancer/tumour" Risk for general population updated to include AIHW 2016 data Cancer risk management guidelines: Heading changed to "Cancer/tumour risk management guidelines" Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk."  Surveillance: "Age to begin" changed to "Age"  Updated link to "COSA - Medications to lower the risk of breast cancer: clinician guide" (also updated link in evidence section) Other table formatting changes Website resources: added link to "COSA - Medications to lower the risk of breast cancer: clinician guide" and "COSA - Medications to lower the chance of breast cancer: information for women".

Version 5

Date	Summary of changes
26/03/2014	Discussed at October 30 2013 & March 5 2014 reference committee meetings and approved for publication. review second yearly
31/07/2015	AGSA link updated to Genetic Alliance Australia.
07/01/2016	Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016	Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
11/07/2016	Discussed at March 2016 reference committee meeting and the following changes made: 7271T>G changed to c.7271T>G throughout document. Evidence for cancer risk management guidelines for breast cancer updated.  Review second yearly.
28/09/2016	'Unaffected' removed from title.
31/05/2017	Transferred to new eviQ website. Version number changed to V.3.
19/09/2017	Discussed at May 2017 reference committee meeting and formally reviewed after with the following changes made:  Lifetime risk of cancer figures updated  Minor wording change throughout document  Version number changed to V.4. For annual review.
19/03/2019	Discussed at November 2018 reference committee meeting and the following changes made: Lifetime risk of cancer: aligned risks in table to 70 years updated figures as relevant removed comment re potential for an increased risk of ovarian cancer due to a lack of data Cancer risk management guidelines:  aligned wording with BRCA2 protocol (ID 162) replaced Cancer Australia RR medication resource with COSA RR medication document  Evidence for risk management guidelines: removed RRSO (which is in ID 162) aligned wording re RR medications to CHEK2 protocol (ID TBC) and added risk reduction percentage Support and information: sentence added re counselling mutation carriers on the risk of ataxia-telangiectasia (AT) in offspring Version updated to V4.0, for two yearly review.
28/08/2019	Protocol title changed from 'Risk management for a female ATM  (c.7271T>G) mutation carrier' to 'ATM (monoallelic c.7271T>G) – risk management (female)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.5.