In "real life," Polygenic Risk Scores (PRS) occupy a transitional space: they are scientifically legitimate and potent research tools, but their clinical reality is currently limited by insurance barriers, ancestry biases, and cautious medical guidelines.

1. Scientific Legitimacy: Valid for Risk Stratification Biologically, PRS is "legit." Unlike monogenic testing (which looks for single, high-impact mutations like BRCA1), PRS aggregates thousands of common, low-impact genetic variants to calculate an individual's overall susceptibility to complex diseases.

• Cardiovascular Disease: PRS is highly effective at identifying individuals with elevated risk for coronary artery disease (CAD) who are invisible to standard screening tools. For example, Mass General Brigham recently launched a clinical test for eight cardiovascular conditions, noting that high polygenic risk can be equivalent to monogenic risk factors. New studies indicate PRS can improve the accuracy of the American Heart Association's PREVENT tool, potentially identifying 3 million high-risk Americans currently missed by standard assessments.

• Breast Cancer: PRS explains over 30% of breast cancer heritability. It can effectively stratify women into risk categories, potentially guiding earlier screening (e.g., MRI) for those in the top deciles of risk.

2. The Ancestry Gap: A Critical Flaw A major hurdle to "legitimacy" for all patients is the ancestry gap. Most PRS were developed using data from European populations. Consequently, these scores are consistently less accurate for individuals of African, Asian, and Hispanic descent. Using a European-derived PRS on a non-European patient can result in misleading risk assessments, potentially exacerbating health disparities. Newer methods, such as "multiple-ancestry PRS" (MA-PRS) and data from the All of Us Research Program, are actively addressing this by recalibrating scores for diverse populations.

3. Clinical and Economic Reality Despite the scientific promise, the "real life" application is restricted by medical guidelines and reimbursement policies:

• Guidelines: The National Comprehensive Cancer Network (NCCN) currently discourages the use of PRS for routine breast cancer risk assessment, citing the need for further validation regarding how these scores interact with environmental factors and their performance in diverse populations. Similarly, the American College of Medical Genetics (ACMG) notes that limited evidence exists to support PRS-guided medical management.

• Insurance Coverage: Major insurers, including UnitedHealthcare and Blue Cross Blue Shield, classify PRS as "unproven," "investigational," or "not medically necessary". They cite a lack of prospective evidence proving that PRS testing leads to improved net health outcomes (clinical utility).

• Access: Consequently, PRS is largely available only through self-pay mechanisms (e.g., the Mass General Brigham test) or participation in large research biobanks like Geisinger’s MyCode or Mount Sinai’s BioMe.

Summary PRS is a legitimate biological measure that works well for risk stratification in specific populations. However, until guidelines endorse its utility and insurers cover the cost, its "reality" remains a self-pay, elective service rather than a standard component of routine healthcare