What breast cancer surveillance and risk‑reduction management is recommended for a patient with a pathogenic ATM mutation and a strong family history of breast cancer, whose family also carries TMEM127 variants?

Breast Surveillance and Management for ATM Pathogenic Variant with Strong Family History

For a patient with a pathogenic ATM mutation and strong family history of breast cancer, enhanced breast surveillance with annual mammography and breast MRI starting by age 40 (or earlier based on family history) is recommended, while risk-reducing mastectomy is generally NOT recommended despite the strong family history. 1

Key Management Principles

Breast Surveillance Strategy

The ATM pathogenic variant alone does not fully explain a striking family history of breast cancer, and surveillance recommendations should be based on personalized risk assessment rather than the genetic result alone. 1

• Enhanced breast surveillance should be offered according to personalized risk estimates using tools like the CanRisk model that incorporate family history, the ATM variant, and other risk modifiers. 1

• Annual mammography should begin by age 40 at the latest, with consideration for earlier initiation based on the strong family history. 2

• Annual breast MRI in addition to mammography should be considered if the calculated lifetime risk is ≥20-25%, which is likely given the combination of ATM mutation and strong family history. 3, 2

• For patients with very strong family history, screening with both MRI and mammography may be warranted starting earlier than age 40. 2

Risk-Reducing Surgery Considerations

Risk-reducing mastectomy is generally NOT recommended for ATM carriers, even in the context of strong family history. 1

• ATM is classified as a moderate-penetrance gene with approximately 2- to 3-fold increased breast cancer risk (lifetime risk ~25%), which is substantially lower than BRCA1/2. 1, 4

• The 2025 ACMG guidelines explicitly state that risk-reducing mastectomy is generally not recommended for ATM heterozygotes, distinguishing them from high-penetrance genes like BRCA1/2. 1

• The strong family history may indicate other unidentified genetic or familial factors beyond the ATM mutation, but this does not change the recommendation against prophylactic mastectomy for ATM alone. 1

TMEM127 Variant Considerations

The TMEM127 variant in the family is not relevant to breast cancer management, as TMEM127 is associated with pheochromocytoma/paraganglioma syndromes, not breast cancer predisposition. The breast surveillance should be guided solely by the ATM mutation and family history. 1

Additional Cancer Surveillance

Pancreatic Cancer Screening

• Pancreatic cancer surveillance should be considered given the ATM mutation, ideally as part of a clinical trial or according to country-specific guidelines. 1

• This is particularly relevant if there is family history of pancreatic cancer, as ATM confers a 4-fold increased risk. 4

Prostate Cancer Screening (if male family members)

• Prostate cancer surveillance should be considered for male ATM carriers, given the 2.5-fold increased risk. 1, 4

Critical Counseling Points

Family History Context

Personalized rather than generalized advice is required, as cancer risks are strongly influenced by family history and other non-ATM genetic factors. 1

• The ATM mutation likely does not fully account for the strong family history, suggesting possible additional genetic factors or chance clustering. 1

• Family members should undergo individualized risk assessment rather than assuming the ATM mutation explains all family risk. 1

Genetic Counseling Essentials

• Partner testing should be offered to assess risk of autosomal recessive ataxia-telangiectasia in offspring (approximately 1 in 800 risk with unrelated partner). 1

• Discussion of reproductive options including preimplantation genetic testing should be included if family planning is relevant. 1

Common Pitfalls to Avoid

• Do not recommend risk-reducing mastectomy based on ATM status alone, even with strong family history—this is a key distinction from BRCA1/2 management. 1

• Do not assume the ATM mutation explains the entire family history—additional genetic testing or risk factors may be present. 1

• Do not use radiation therapy concerns to influence treatment decisions—the 2025 ACMG guidelines state that radiation therapy decisions should NOT be influenced by ATM carrier status. 1

• Do not overlook pancreatic and prostate cancer risks when counseling about the broader cancer spectrum associated with ATM. 1, 4