What Is Germline Genetic Testing And How Does It Work?

Germline genetic testing looks at DNA you inherited from your parents to find changes that increase your risk for certain diseases, especially cancer. Unlike tumor testing which only looks at cancer cells, germline testing checks every cell in your body because the genetic change is in your bloodline. The test uses a blood or saliva sample to read specific genes and identify mutations that can be passed down to children.

What Is Germline Genetic Testing And How Does It Work?

Germline genetic testing analyzes DNA from your normal cells, not from a tumor. The word “germline” refers to the egg and sperm cells that carry genetic information from one generation to the next. When a mutation is in the germline, it exists in every cell of your body and can be inherited by your children.

The process starts with a blood draw or saliva sample. A lab extracts DNA from your white blood cells or cheek cells and sequences specific genes. Most tests today use next-generation sequencing, which reads thousands of genes at once. The lab compares your DNA sequence to a reference genome to find differences that could cause disease.

Results typically take two to four weeks. A positive result means a disease-causing mutation was found. A negative result means no mutation was detected in the genes tested. A variant of uncertain significance means the lab found a DNA change but does not know yet if it causes disease.

Who Should Consider Germline Genetic Testing?

The National Comprehensive Cancer Network recommends germline testing for people with certain personal or family cancer histories. This includes people diagnosed with breast cancer before age 50, ovarian cancer at any age, pancreatic cancer, metastatic prostate cancer, or colorectal cancer before age 50. Multiple family members with the same cancer type or a known genetic mutation in the family also qualify.

Testing is not recommended for everyone. The CDC estimates that about 5 to 10 percent of all cancers are caused by inherited genetic mutations. For someone with no family history and no personal cancer diagnosis, the chance of finding a meaningful mutation is very low. False positives and variants of uncertain significance can cause unnecessary worry and medical procedures.

Genetic counselors play a key role here. They take your detailed family history, explain what results could mean, and help you decide if testing is right for you. The American College of Medical Genetics and Genomics recommends pre-test counseling for anyone undergoing germline testing.

What Cancers Are Linked to Germline Mutations?

BRCA1 and BRCA2 mutations are the most well-known germline mutations. Research published in JAMA found that women with a BRCA1 mutation have a 55 to 72 percent lifetime risk of breast cancer and a 39 to 44 percent risk of ovarian cancer. For BRCA2, the breast cancer risk is 45 to 69 percent and ovarian cancer risk is 11 to 17 percent.

Other common germline mutations include Lynch syndrome genes like MLH1, MSH2, MSH6, and PMS2. These increase risk for colorectal, endometrial, ovarian, and other cancers. People with Lynch syndrome have a 40 to 80 percent lifetime risk of colorectal cancer, according to the National Cancer Institute.

Less common but significant mutations include TP53 which causes Li-Fraumeni syndrome, CDH1 which increases stomach and breast cancer risk, and STK11 which causes Peutz-Jeghers syndrome. Each syndrome comes with its own set of cancer risks and screening recommendations.

How Is Germline Testing Different From Tumor Testing?

Tumor testing, also called somatic testing, looks at the DNA inside a cancer tumor. This reveals mutations that developed in the cancer cells themselves. Germline testing looks at your normal cells to find inherited mutations present from birth. The two tests answer different questions.

A person can have a germline mutation that did not cause their current cancer but increases their risk for a second cancer. Tumor testing would not find this. Conversely, a tumor might have a mutation that is not present in the germline at all. The mutation happened only in the cancer cells.

Some people get both tests. A 2020 study in the Journal of Clinical Oncology found that about 8 percent of people with advanced cancer had germline mutations that were not detected by tumor testing alone. This is why guidelines now recommend germline testing for certain cancers regardless of tumor testing results.

What Do Germline Test Results Mean For Family Members?

A positive germline test result has implications beyond the person tested. Each child has a 50 percent chance of inheriting the mutation. Siblings also have a 50 percent chance. This is called autosomal dominant inheritance, which applies to most hereditary cancer syndromes.

Family members who test negative for the known mutation can stop extra screening. They have the same cancer risk as the general population. Family members who test positive can begin earlier and more frequent screening, consider risk-reducing surgeries, or take chemoprevention drugs.

The CDC recommends that anyone with a positive germline test result share this information with their blood relatives. Genetic counselors can provide letters and resources to help with this conversation. Some families find this difficult emotionally, but it can save lives through early detection or prevention.

What Are The Limitations And Risks Of Germline Testing?

Germline testing does not detect all genetic mutations. Most panels test for known pathogenic mutations in specific genes. If you have a mutation in a gene not included on the panel, the test will come back negative. This is called a false negative. About 50 percent of families with strong cancer histories still have no identifiable mutation.

Variants of uncertain significance create confusion. A 2021 study in Genetics in Medicine found that about 2 percent of germline tests return a VUS. Over time, as more data accumulates, some VUS are reclassified as benign or pathogenic. But in the moment, patients and doctors must decide what to do with uncertain information.

Insurance discrimination is a real concern. The Genetic Information Nondiscrimination Act of 2008 protects against health insurance and employment discrimination based on genetic test results. However, GINA does not cover life insurance, disability insurance, or long-term care insurance. Some people choose to purchase these policies before getting tested.

How Accurate Is Germline Genetic Testing?

Clinical germline testing is highly accurate when done by certified laboratories. The College of American Pathologists accredits labs that meet strict quality standards. Sensitivity for detecting known pathogenic mutations in the genes tested exceeds 99 percent.

Accuracy depends on the technology used. Sanger sequencing was the gold standard for decades and remains highly accurate for single genes. Next-generation sequencing can test many genes at once but has slightly higher error rates for certain types of mutations. Labs confirm important findings with a second method.

False positives are rare but possible. A 2019 study in JAMA Network Open found that about 0.1 percent of germline test results were false positives due to sample mix-ups or technical errors. Confirmatory testing on a second sample can resolve these cases.

What Happens After A Positive Germline Test Result?

A positive result leads to a specific management plan. For BRCA carriers, this includes breast MRI starting at age 25, mammograms starting at age 30, and discussion of risk-reducing salpingo-oophorectomy between ages 35 and 40. For Lynch syndrome, colonoscopy every one to two years starting at age 25 is standard.

Risk-reducing surgeries are an option but not a requirement. Many people choose enhanced screening instead. A 2022 study in the New England Journal of Medicine found that prophylactic mastectomy reduces breast cancer risk by 90 to 95 percent in BRCA carriers. Oophorectomy reduces ovarian cancer risk by 80 to 96 percent.

Chemoprevention is another option. Tamoxifen and raloxifene can reduce breast cancer risk in high-risk women. Aspirin has been shown to reduce colorectal cancer risk in people with Lynch syndrome. A doctor or genetic counselor can help weigh the benefits and risks of each approach.