What are the genetic mutations associated with breast cancer, including their risks and penetrance, and what is BRCAness in a woman with a family history of breast cancer?

Genetic Mutations Associated with Breast Cancer: Risks, Penetrance, and BRCAness

High-Penetrance Genes (Up to 80% Lifetime Risk)

BRCA1 and BRCA2 mutations confer a 50-85% lifetime risk of breast cancer and account for up to 25% of hereditary breast cancer cases, with BRCA1 carriers typically developing triple-negative tumors while BRCA2-related tumors resemble sporadic cancers. 1

BRCA1 and BRCA2

• Lifetime breast cancer risk: 50-85% for female carriers 1
• Ovarian cancer risk: 10-40% for BRCA1 carriers; 10-20% for BRCA2 carriers 1
• Male breast cancer risk: Minimal for BRCA1; 5-10% for BRCA2 carriers 1
• Tumor characteristics: BRCA1 tumors are typically triple-negative (ER-, PR-, HER2-), high-grade, basal-like phenotype; BRCA2 tumors resemble sporadic breast cancers 1
• Inheritance pattern: Autosomal dominant with tumor suppressor function involving double-stranded DNA repair 1
• Founder mutations: Three major mutations in Ashkenazi Jewish population (BRCA1.185delAG, BRCA1.5382insC, BRCA2.6174delT) account for ~10% of hereditary cases in this population 1

Other High-Penetrance Genes

• PTEN (Cowden Syndrome): 85% lifetime breast cancer risk, plus nonmedullary thyroid cancer, endometrial cancer, and characteristic skin lesions 1, 2
• TP53 (Li-Fraumeni Syndrome): 25% breast cancer risk by age 74, plus sarcoma, brain tumors, adrenocortical carcinoma, and leukemia 1, 2
• CDH1 (Hereditary Diffuse Gastric Cancer): 39% lifetime risk of lobular breast cancer, plus diffuse gastric cancer and colorectal cancer 1, 2
• STK11 (Peutz-Jeghers Syndrome): 32% breast cancer risk by age 60, plus GI cancers, pancreatic cancer, and sex-cord stromal tumors 1, 2

Moderate-Penetrance Genes (Approximately 2-fold Increased Risk)

Moderate-penetrance genes including CHEK2, ATM, PALB2, and BRIP1 account for only 2-3% of hereditary breast cancer cases, each conferring approximately a twofold increase in risk. 1

• CHEK2: Twofold increased risk, with founder effects in certain populations 1, 2
• ATM: Relative risk of 2.3, higher for women under age 50; biallelic mutations cause ataxia-telangiectasia 1, 2
• PALB2: Relative risk of 2.3 overall, 3.0 for women under 50; associates with BRCA2 in DNA repair; biallelic mutations cause Fanconi anemia type N 1, 2
• BRIP1: Twofold increased risk 1, 2

Clinical Management for Moderate-Penetrance Mutations

Women with moderate-penetrance gene mutations require risk assessment using models like Tyrer-Cuzick or BOADICEA that incorporate personal and family history, as these mutations confer lower lifetime risk than high-penetrance genes. 1

• Annual breast MRI recommended if calculated lifetime risk ≥20% 1
• Clinical breast examination every 6 months for all women with increased lifetime risk 1
• The Gail model is inadequate for MRI screening justification as it only includes first-degree family history 1

Low-Penetrance Alleles

Single-nucleotide polymorphisms (SNPs) contribute to breast cancer risk in a polygenic fashion, but individual SNP contribution is quite small and requires genome-wide studies with thousands of cases to detect. 1

• Common variants with minimal individual risk contribution 1
• Require stringent P-value thresholds (P = 5 × 10⁻⁸) for genome-wide significance 1
• Not currently used for clinical risk assessment 1

BRCAness: The Clinical Phenotype

BRCAness refers to the clinical syndrome of Hereditary Breast/Ovarian Cancer (HBOC) that occurs in patients who test negative for BRCA1 and BRCA2 mutations but present with the same clinical picture, representing the majority of hereditary breast cancer cases. 1

Key Characteristics of BRCAness

• Prevalence: Specific predisposing genes identified in <30% of cases with suggestive personal/family history 1
• Unexplained cases: >70% of familial breast cancer cases remain genetically unexplained despite testing 2
• Clinical significance: Women with strong family history but negative BRCA testing have approximately 4-fold increased breast cancer risk 3
• Age-specific risks: Highest standardized incidence ratio (14.9) for women under age 40, but absolute risk peaks at 1% per year between ages 50-70 3

Mechanisms Underlying BRCAness

• Unknown or undiscovered genes likely contribute to hereditary cancer risk 2
• Genetic testing sensitivity <100%, meaning mutations can be missed 2
• Large genomic rearrangements may not be detected by standard sequencing 2
• Fewer than one-third of excess breast cancers in relatives of young case patients are BRCA1/BRCA2-related 4

Critical Clinical Pitfalls to Avoid

Never falsely reassure patients based on negative BRCA testing alone when strong family history persists, as this represents the most dangerous clinical error in hereditary breast cancer assessment. 2

• Testing limitations: Current genetic testing identifies causative mutations in <30% of hereditary cases 1, 2
• Family history remains paramount: Risk assessment must incorporate complete three-generation pedigree regardless of genetic test results 2
• Repeat testing indicated: Consider retesting as new genes are discovered and methods improve 2
• Small family size masking: Predominance of male relatives or small family size can obscure hereditary predisposition 2
• Specialist referral essential: Patients with strong family history require cancer genetics specialist consultation even with negative testing 2

Risk Assessment Tools for Clinical Practice

Primary care providers should use brief familial risk stratification tools including the Referral Screening Tool or FHS-7 (sensitivity >85%) to determine need for genetic counseling, not general breast cancer risk models like the Gail model. 1

High-Risk Features Warranting Genetic Counseling

• Breast cancer diagnosis before age 50 1
• Bilateral breast cancer 1
• Breast and ovarian cancer in family 1
• Male breast cancer in family 1
• Multiple breast cancers in family 1
• Ashkenazi Jewish ethnicity with any affected relative 1

Management Recommendations

• Screening initiation: Age 25 for high-risk gene carriers, with clinical breast exam and imaging (mammography plus MRI) starting at age 25 or 10 years before youngest family case 1
• Risk-reducing surgery: Mastectomy reduces breast cancer risk by 85-100%; salpingo-oophorectomy reduces ovarian cancer risk by 69-100% and all-cause mortality by 55% in BRCA carriers 1
• Chemoprevention: Tamoxifen and raloxifene reduce invasive breast cancer in high-risk women, though not specifically studied in BRCA carriers 1
• Annual reassessment: Family history should be comprehensively reviewed at least every 5-10 years, with updates when new cancer events occur 1, 2