BRCA Mutations and Cancer Risk in Men: Important but Overlooked

The well-established association of pathogenic BRCA1 and BRCA2 variants with breast and ovarian cancer in women has led to strong clinical guidance for early genetic testing and risk reduction.

Genes are segments of DNA carrying genetic information. A gene is a DNA sequence encoding a particular protein or functional RNA molecule. Genes determine many biological traits, from eye color and hair structure to disease susceptibility and metabolism.

What Is a Pathological Gene Variant?

A gene's “pathological” or “pathogenic” variant is an altered form that differs from normal. Such variants may disrupt normal gene function and cause disease. For example, pathogenic BRCA1 and BRCA2 variants may impair cells' ability to repair DNA damage, increasing breast and ovarian cancer risk.

Inherited and Somatic Pathogenic Variants: What Is the Difference?

• Inherited Pathogenic Variants: These pass from parents to children and are present in all a person's cells. They exist from birth and can be transmitted through generations. Pathogenic BRCA1 and BRCA2 variants are generally inherited and therefore associated with familial cancer syndromes.

• Somatic Pathogenic Variants: These arise in particular cells during life and are not inherited. They may develop through external influences such as environmental factors, chemicals, or radiation, leading to diseases such as cancer arising from that cell. They are present only in affected cells and do not pass to the next generation.

In short, inherited pathogenic variants run in families, while somatic pathogenic variants develop during life and are not inherited.

A pathological gene variant is therefore a DNA change that adversely affects gene function and can lead to disease.

BRCA1/2 Mutations in Men

Male carriers of pathogenic BRCA1/2 variants also face increased risks of prostate, pancreatic , and breast cancer in particular.

Men, however, are often overlooked.

• Related Topic: Unraveling the Genetics of Male Breast Cancer

Although men account for half of pathogenic BRCA1/2 variant carriers, they are far less likely to undergo BRCA testing. In a comprehensive review published on July 25, 2024, in JAMA Oncology, Dr. Heather Cheng of the University of Washington in Seattle and colleagues explained, “Most people, including clinical specialists, are unaware of their carrier status. Most doctors also lack knowledge of the associated cancer risks and management recommendations for BRCA carriers.”

The testing gap in men may partly reflect a “general lack of awareness” that BRCA mutations can pass to children from either parent. Daughters can inherit a mutated BRCA gene from their mother or father, placing them at risk of breast or ovarian cancer. Sons can similarly inherit these genes and face increased prostate and other cancer risks.

Family history and genetics on both sides of the family are crucial when assessing cancer risk in men and women.

BRCA Mutations in Men: What Are the Risks?

Although fewer than 1% of all breast cancers occur in men, risk increases significantly in male BRCA mutation carriers. Lifetime breast cancer risk may reach 9% in male BRCA2 carriers and 1.2% in BRCA1 carriers.

BRCA1/2 mutations also increase pancreatic and prostate cancer risk in men.

For pancreatic cancer, BRCA1 carriers have approximately 2 times the general population's risk, with a lifetime risk of 3%. In BRCA2 carriers, risk increases three- to eightfold, with lifetime risk reaching 7%.

For prostate cancer, BRCA1 carriers have nearly fourfold increased risk, with lifetime absolute risk ranging from 15% to 45%. BRCA2 carriers have five- to ninefold increased risk, with lifetime absolute risk ranging from 27% to 60%.

When Should Genetic Testing and Screening Be Performed?

Despite increased risks of several BRCA-associated cancers, many men are not offered genetic testing.

BRCA1/2 testing in men is considered “critically important but underused,” representing a significant unmet need.

Barriers men may face when considering testing include fears that insurance will not cover it, that a positive result may raise premiums, and concerns about what results mean for themselves and their families.

• Related Topic: Psychological Effects of Hereditary Cancer Screening (Genetic Tests)

Even for confirmed BRCA carriers, cancer screening guidelines for men vary.

There are insufficient data to inform male breast cancer screening guidelines. The National Cancer Center Network (NCCN) currently recommends breast awareness and self-examination education from age 35. It advises men with BRCA variants to consider annual mammography from age 50 or 10 years before the family's earliest male breast cancer diagnosis.

Data show similar cancer detection rates with screening mammography in high-risk men and women, suggesting it may be valuable for male BRCA carriers. In one study of men with pathogenic BRCA1/2 variants, most of those offered screening mammography (71%) completed it.

Not Just Breast Cancer

Despite increased risks of several BRCA-associated cancers, many men are not offered genetic testing.

BRCA1/2 testing in men is considered “critically important but underused,” representing a significant unmet need.

Barriers men may face when considering testing include fears that insurance will not cover it, that a positive result may raise premiums, and concerns about what results mean for themselves and their families.

Even for confirmed BRCA carriers, cancer screening guidelines for men vary.

There are insufficient data to inform male breast cancer screening guidelines. The National Cancer Center Network (NCCN) currently recommends breast awareness and self-examination education from age 35. It advises men with BRCA variants to consider annual mammography from age 50 or 10 years before the family's earliest male breast cancer diagnosis.

Data show similar cancer detection rates with screening mammography in high-risk men and women, suggesting it may be valuable for male BRCA carriers. In one study of men with pathogenic BRCA1/2 variants, most of those offered screening mammography (71%) completed it.