Genetic Testing for Cancer Risk: Complete Guide to Hereditary Cancer
Genetic testing for cancer risk analyzes genes like BRCA1, BRCA2, Lynch syndrome genes (MLH1, MSH2), and TP53 to identify inherited mutations that increase cancer susceptibility. If multiple family members developed cancer at young ages or you have specific patterns (breast and ovarian clustering), testing determines whether hereditary cancer syndromes explain your family history and guides screening strategies.
This guide covers hereditary cancer testing science, who qualifies based on family history, cancer predisposition genes beyond BRCA, and evidence-based actions after receiving results. You'll learn about oncogenetics, cancer risk assessment, and familial cancer genetics informing clinical decisions.
📋 Educational Content Disclaimer
This article provides educational information about genetic variants and is not intended as medical advice. Always consult qualified healthcare providers for personalized medical guidance. Genetic information should be interpreted alongside medical history and professional assessment.
Understanding Hereditary Cancer: Genes and Risk
Hereditary cancer syndromes account for 5-10% of all cancers, occurring when you inherit a germline mutation in cancer predisposition genes. Unlike somatic mutations developing in cells, germline mutations exist in every body cell from conception and pass to children with 50% probability. BRCA1/2 mutations increase lifetime breast cancer risk to 45-72% (versus 12-13% baseline) and ovarian cancer risk to 11-40% (versus 1-2%). Lynch syndrome elevates colorectal cancer risk to 50-80% and endometrial cancer risk to 25-60% by age 70.
Cancer genes fall into high-penetrance and moderate-penetrance categories. High-penetrance genes like TP53 (Li-Fraumeni), PTEN (Cowden syndrome), and CDH1 (diffuse gastric cancer) confer 60-90% lifetime cancer risk across multiple organs. Moderate-penetrance genes like CHEK2, PALB2, and ATM increase risk 2-4 fold.
Hereditary cancer follows autosomal dominant inheritance—one mutated copy from either parent suffices. Suggestive patterns include multiple relatives with same cancer, diagnoses before age 50, bilateral cancers, rare cancers (male breast cancer), and multiple primaries in one person. Ashkenazi Jewish populations show 10-fold higher BRCA prevalence (1 in 40 versus 1 in 400).
Who Should Get Cancer Genetic Testing
National Comprehensive Cancer Network guidelines recommend testing for specific personal or family history criteria. Personal criteria include breast cancer before age 45, triple-negative breast cancer before 60, ovarian cancer at any age, male breast cancer, pancreatic cancer with Jewish ancestry, metastatic prostate cancer, or colorectal/endometrial cancer with microsatellite instability. Each criterion reflects mutation prevalence exceeding 5-10%.
Family history criteria focus on multi-generation patterns. Testing applies if you have two+ relatives with breast cancer (one before 50), any ovarian cancer relative, three+ relatives with Lynch-associated cancers, one first-degree relative meeting personal criteria, or a known familial variant. First-degree relatives share 50% of genes; second-degree share 25%.
Testing costs range from $250-5,000 depending on panel breadth. Affordable Care Act insurance covers BRCA testing when criteria are met with no cost-sharing. Medicare covers medically necessary testing. Many labs offer assistance reducing costs to $100-250. Genetic counseling ($200-300) is recommended before testing.
If you have 23andMe, AncestryDNA, or clinical data and want to explore cancer-related variants more deeply, explore your cancer genetics with Ask My DNA. Ask questions like "which cancer genes show variants in my data" or "does my TP53 status suggest specific screening" based on your actual genetics.
Common Cancer Genes: BRCA, Lynch, TP53, and More
BRCA1 and BRCA2 encode proteins essential for DNA repair. Over 1,000 pathogenic variants have been catalogued. Ashkenazi founder mutations (BRCA1 185delAG, 5382insC; BRCA2 6174delT) account for >90% of mutations in that population. Testing uses next-generation sequencing for point mutations and large rearrangements. Beyond breast/ovarian cancer, BRCA2 increases pancreatic risk 3-5 fold and prostate risk 2-8 fold.
Lynch syndrome results from mutations in mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM deletion. MLH1/MSH2 mutations cause highest risks (50-80% colorectal, 40-60% endometrial); MSH6/PMS2 show lower penetrance but require surveillance. Tumor testing with immunohistochemistry or microsatellite instability identifies likely mutated genes. Lynch increases risks for colorectal, endometrial, ovarian, gastric, pancreatic, urinary tract, brain, and sebaceous cancers.
TP53 (Li-Fraumeni) mutations affect the "guardian of the genome," causing 90% lifetime cancer risk (women) and 70% (men). Classic features include early-onset breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, and adrenocortical carcinoma. Surveillance includes whole-body MRI annually from childhood. Other high-penetrance genes include PTEN (Cowden: breast, thyroid, endometrial, renal cancers plus macrocephaly), CDH1 (70% gastric cancer by 80, 40-50% lobular breast cancer), and STK11 (Peutz-Jeghers: hamartomatous polyps, 90% lifetime cancer risk).
After Testing Positive: Screening and Prevention Options
Enhanced surveillance significantly reduces mortality per NCCN guidelines. For BRCA1/2 carriers, breast surveillance includes monthly self-exams from age 18, clinical exams every 6-12 months from 25, annual breast MRI from 25-30 (71-100% detection versus 16-40% mammography), and annual mammography from 30. Ovarian surveillance combines transvaginal ultrasound and CA-125 every 6 months from 30-35, though mortality benefit is unproven. Pancreatic surveillance (MRI/endoscopic ultrasound) applies for BRCA2 carriers with family pancreatic history.
Risk-reducing surgeries offer most effective prevention. Bilateral prophylactic mastectomy reduces breast cancer risk 90-95% but involves quality-of-life considerations: body image, sensation, reconstruction complications (infection, capsular contracture, 10-40% implant failure over 10 years). Salpingo-oophorectomy decreases ovarian risk 80-90% and breast risk 40-50% premenopausally but induces surgical menopause with bone density loss, cardiovascular changes, and sexual function impacts.
Chemoprevention provides medical risk reduction. Tamoxifen and raloxifene reduce breast cancer 40-50% but increase venous thromboembolism 2-3 fold and endometrial cancer 2-3 fold (tamoxifen only). Aspirin reduces colorectal cancer 30-40% in Lynch carriers after 2+ years (600mg daily in trials) with bleeding risks. Oral contraceptives decrease ovarian cancer 40-50% with 5+ years use in BRCA carriers, though slight breast cancer increase (1.1-1.2 relative risk) requires individual assessment.
Frequently Asked Questions
Does a positive test mean I will definitely get cancer?
No, pathogenic variants increase risk significantly but don't guarantee cancer. BRCA1 mutations confer 45-72% lifetime breast cancer risk, meaning 28-55% of carriers never develop breast cancer. Penetrance varies by specific mutation, family history, modifier genes, and environmental factors (reproductive history, weight, alcohol). Enhanced surveillance detects cancers early when most curable, while prevention strategies like surgeries further decrease incidence.
Can testing detect all hereditary cancers in my family?
Current panels test 30-80 known cancer genes but can't detect all genetic causes of familial clustering. Approximately 50-60% meeting hereditary breast/ovarian criteria receive negative results, suggesting undiscovered genes, polygenic risk, shared environment, or chance. Negative results don't eliminate familial risk; high-risk screening may still apply based on family history alone. Testing identifies variants in 10-15% of breast cancer patients and 5-10% of colorectal patients meeting criteria.
Will testing affect my insurance or employment?
The Genetic Information Nondiscrimination Act (GINA) prohibits health insurers and employers from genetic discrimination in the US. Health insurers can't deny coverage, adjust premiums, or determine preexisting conditions using genetic results. Employers can't use genetic information for hiring, firing, or promotions. GINA doesn't protect against life, disability, or long-term care insurance discrimination—these may request results and adjust coverage. Some states provide additional protections beyond GINA.
Should family members get tested if I have a mutation?
Yes, first-degree relatives have 50% probability of inheriting the mutation and should receive genetic counseling. Cascade testing (sequential relative testing) is most cost-effective—relatives undergo targeted single-site testing ($200-500) rather than comprehensive panels once familial mutation is identified. Children shouldn't be tested for adult-onset genes until age 18 unless syndrome includes childhood risks (TP53 Li-Fraumeni). Negative relatives receive reassurance and follow general-population screening rather than high-risk protocols.
Understanding cancer genetic testing results enables evidence-based decisions about surveillance, prevention, and family communication. Whether considering testing or interpreting results, genetic counseling supports navigating medical, psychological, and familial implications of hereditary cancer genetics.