ATM (monoallelic pathogenic variants) – risk management

Familial breast cancer predisposition due to a germline pathogenic variant in the ATM gene is an autosomal dominant condition. Most monoallelic pathogenic variants in ATM are estimated to be associated with a moderately increased risk of breast cancer (two-to threefold increased risk).^rrr ATM c.7271T>G is associated with a higher risk of breast cancer that is similar to that associated with a germline BRCA2 pathogenic variant.^rr 

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.

• Unaffected known or obligate ATM pathogenic variant carrier
• 50% risk of being an ATM pathogenic variant carrier

Exclusion criteria

• Female ATM pathogenic variant carriers affected by breast cancer
• Individuals with a pathogenic variant in another breast cancer predisposition gene 
• High risk breast cancer family with uninformative genetic test result or no DNA testing available
• High risk breast and ovarian cancer family with uninformative genetic test result or no DNA testing available
• Individuals with a 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. It is important to note that the validated risk prediction tool CanRisk has the potential to underestimate risk associated with the particular 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.

Cancer/tumour type	Recommendations
Breast	Surgical	Offer bilateral risk-reducing mastectomy. The greatest benefit would be predicted when surgery occurs at age <40 years
	Surveillance	In families with breast cancer diagnosed under age 35 years individualised screening recommendations may apply. Otherwise screening should start at age 30 years
		Age	Strategy and frequency
		30-40 years	Annual MRI, +/- US
		40-50 years	Annual MRI, +/- MMG, +/- US
		Over age 50 years	Annual MMG, +/- US (Consider MRI if over age 50 years with dense breast tissue)
		Pregnant	No MRI or MMG, consider US
	Risk-reducing medication	Consider use of medication to reduce risk of developing breast cancer: Pre-menopausal women from age 35 years may consider tamoxifen Post-menopausal women may consider raloxifene, aromatase inhibitors or tamoxifen Requires assessment of risks and benefits for an individual woman by an experienced medical professional. See COSA - Medications to lower the risk of breast cancer: clinician guide
Pancreatic	Surveillance	No evidence of benefit from surveillance
Prostate	Surveillance	No evidence of benefit from surveillance

Abbreviations: MRI - magnetic resonance imaging, US - ultrasound, MMG - mammogram

Breast

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

Bilateral risk reducing mastectomy reduces breast cancer risk by at least 90%^rr (depending on the operation performed). Statistically significant survival benefit associated with bilateral risk-reducing mastectomy compared with surveillance is yet to be demonstrated. 

Surveillance

MRI+MMG is the preferred screening technique due to its high sensitivity. MRI detects tumours which are smaller and more likely to be node-negative than mammography. 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%.

There is no evidence to date that early detection of breast cancer is associated with a better prognosis and survival in ATM pathogenic variant carriers. Despite this lack of evidence, surveillance is strongly recommended for women who decide not to have risk reducing surgery. 

Risk-reducing medication

Selective oestrogen receptor modulators (SERM), such as tamoxifen, 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 with 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.

In view of the potential side effects, risk-reducing medications should be discussed with an experienced medical professional to determine the relevant risks and benefits in an individual pathogenic variant carrier. See COSA – Medications to lower the risk of breast cancer: clinician guide.

Pancreatic

There is currently no effective surveillance that detects early pancreatic cancer. Refer to Australian Pancreatic Cancer Genome Initiative website for up-to-date screening trials.

Prostate

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

Radiation therapy

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. 

Breast

At the present time, and while there is no specific evidence related to other ATM pathogenic variant carriers, these guidelines are based on those that apply to management of breast cancer risk in women at moderately increased risk. 

Pancreatic

There is currently no effective surveillance that detects early pancreatic cancer. Refer to Australian Pancreatic Cancer Genome Initiative website for up-to-date screening trials.

Prostate

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

Radiation therapy

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. 

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 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 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.