What are the management guidelines for individuals with Ataxia-Telangiectasia Mutated (ATM) gene mutations?

Management Guidelines for ATM Gene Mutations

For individuals with ATM gene mutations, management should be based on an individualized risk assessment using models such as CanRisk, with most heterozygotes qualifying for enhanced breast surveillance and some meeting criteria for breast MRI based on country-specific guidelines. 1, 2

Cancer Risk Assessment and Surveillance

Breast Cancer Management

• Breast cancer surveillance:

  • Enhanced breast surveillance recommended based on personalized risk assessment using CanRisk or similar models 1
  • Most ATM heterozygotes will qualify for enhanced surveillance above population-based screening 1
  • Some will meet criteria for breast MRI based on country-specific guidelines 1
  • Female ATM heterozygotes have approximately 25% lifetime risk of breast cancer, with majority being ER-positive 3
  • Female carriers of the specific c.7271T>G p.(Val2424Gly) variant should begin enhanced surveillance from age 25 due to significantly higher breast cancer risk (up to 60% by age 80) 1, 2, 4

• Risk-reducing mastectomy:

  • Not routinely recommended for ATM heterozygotes 1, 2
  • May be considered based on individualized risk assessment and shared decision-making 1
  • For women with breast cancer and ATM mutation, contralateral risk-reducing mastectomy should not be routinely offered but may be considered based on personalized risk assessment 1

Other Cancer Surveillance

• Pancreatic cancer:

  • Surveillance should be considered, ideally as part of a clinical trial 1, 2
  • Limited evidence for effectiveness of pancreatic cancer screening in ATM carriers 2

• Prostate cancer:

  • Annual PSA testing beginning at age 40 is reasonable 1, 2
  • Digital rectal examination may help interpret PSA findings 2

• Ovarian cancer:

  • Risk-reducing salpingo-oophorectomy (RRSO) is not routinely recommended 1, 2
  • May be considered with family history of ovarian cancer or if gynecological surgery is planned for other reasons 1
  • Lifetime risk of ovarian cancer is approximately 5% 3

Treatment Considerations

Radiation Therapy

• Current consensus is to offer radiation therapy when indicated, without modification based on ATM heterozygote status 1, 2
• No evidence supports avoiding or modifying radiation therapy based on ATM mutation status 1

Targeted Therapies

• Limited evidence for effectiveness of PARP inhibitors in ATM-mutated cancers 1, 2
• Mixed responses observed in clinical trials for ATM-mutated cancers 2

Genetic Counseling and Family Considerations

• Cascade testing of adult family members is appropriate to guide management 1
• Consider partner testing before pregnancy planning, especially with family history of AT or in consanguineous relationships 2
• Discuss preimplantation genetic testing and prenatal diagnosis options 2
• Parents of children with AT are obligate ATM heterozygotes and should receive genetic counseling regarding their cancer risks 1

Special Considerations for Variant Interpretation

• Some specific missense variants like c.7271T>G p.(Val2424Gly) confer significantly higher breast cancer risk than typical truncating variants 1, 2
• Standard risk assessment models may underestimate risks for these higher-risk variants 1, 2
• Variants of uncertain significance (VUS) should not guide clinical management or predictive testing 1, 2
• ATM variants may be reclassified over time as new evidence emerges 1

Lifestyle Recommendations

• All carriers should be made aware of lifestyle factors that contribute to cardiovascular diseases and diabetes 4
• ATM mutation carriers have increased risk of mortality from cancer and ischemic heart diseases (RR 1.7,95% CI 1.2-2.4) 4

Research Gaps

• Prospective data collection needed to establish the full spectrum of ATM-associated cancers 1
• Better evidence needed to determine effectiveness of surveillance, risk-reducing surgery, and cancer treatments in ATM carriers 1
• Development of improved polygenic risk scores and risk models validated across diverse populations is urgently needed 1