Germline genetic testing analyzes inherited DNA to determine a person’s risk for certain conditions, most commonly hereditary cancers. This process involves a series of managed steps, beginning with patient consultation and culminating in the interpretation of complex genetic data. The procedure is designed to accurately identify specific genetic changes, or variants, that were passed down from one’s parents.
Understanding Germline Versus Somatic Testing
Germline testing focuses on the DNA sequence inherited from parents, which is present in virtually every cell of the body, including the reproductive cells. The variants identified through germline testing are therefore considered inherited and can be passed on to future generations. These results provide information about an individual’s lifetime risk for developing a specific disease.
Somatic testing, in contrast, examines genetic changes that are acquired during a person’s lifetime and are typically found only in specific cells, such as those within a tumor. Somatic variants are not inherited and cannot be passed to offspring. The distinction is important because germline results affect not only the patient but also their biological family members.
The type of test determines the sample used and the clinical question being answered. Germline analysis uses readily available healthy cells, while somatic analysis typically requires a tissue biopsy from the affected area. Distinguishing between these two types of variants is a foundational step in genetic medicine, guiding both risk management and treatment decisions.
Pre-Test Counseling and Sample Collection
The pre-test genetic counseling session provides context for the testing. During this meeting, a genetic counselor discusses the potential risks and benefits, including the possibility of receiving uncertain results or implications for other family members. The process of informed consent ensures the patient fully understands the scope of the testing before proceeding.
Once consent is obtained, the sample collection phase begins. Germline DNA can be extracted from any nucleated cell because the genetic code is the same throughout the body. The most common samples collected are a blood sample, or a saliva or cheek swab sample. These methods are simple, non-invasive, and reliably yield high-quality DNA for analysis.
Laboratory Analysis and Sequencing
The collected sample is sent to a specialized laboratory where the DNA is extracted from the cells. The extraction process involves breaking open the cell membranes and purifying the genomic DNA, separating it from proteins and other cellular components. This purified DNA is then measured to ensure there is enough material of sufficient quality for the next steps.
Following extraction, the DNA undergoes a preparation process to create a “library” ready for sequencing. This involves fragmenting the long strands of DNA into smaller pieces and then attaching short synthetic sequences called adaptors to the ends of each fragment. The adaptors are necessary for the DNA fragments to bind to the sequencing platform and for the machine to read the sequence.
Next-Generation Sequencing (NGS) technology is the standard method used to read the genetic code. NGS simultaneously sequences millions of these prepared DNA fragments, reading the order of the four chemical bases—Adenine (A), Cytosine (C), Guanine (G), and Thymine (T). This high-throughput method allows for the comprehensive analysis of many genes, or even the entire genome, in a single test.
The sequencing machine generates massive amounts of raw data, which is then processed using powerful computer programs in a step called bioinformatics. The fragments are aligned to a reference human genome sequence, like assembling a massive jigsaw puzzle, to determine the exact order of the patient’s bases. This alignment process allows specialized software, known as variant callers, to identify any differences between the patient’s sequence and the reference, flagging specific genetic changes or variants.
Interpreting and Communicating Results
Once the variants are identified, they undergo a clinical interpretation process where they are classified based on their suspected impact on health. Expert clinical scientists classify each variant into one of five categories, ranging from pathogenic (disease-causing) to benign (harmless). A key classification is the Variant of Uncertain Significance (VUS), which is a change whose clinical impact is currently unknown due to a lack of available evidence.
The classification process relies on comparing the identified variant against large public and proprietary databases and applying established guidelines, such as those from the American College of Medical Genetics and Genomics (ACMG). The final report synthesizes these findings, detailing the identified pathogenic or likely pathogenic variants and their associated disease risks. This report is then delivered to the ordering healthcare provider.
Post-test genetic counseling is the final step, where the genetic counselor communicates the results to the patient in an understandable way. They explain the clinical significance of any findings, discuss the implications for the patient’s family, and outline recommended next steps. These steps often include increased screening, preventative measures, or referral to specialists.