GENETIC DUTIES.

• Author: Roberts, Jessica L.

TABLE OF CONTENTS INTRODUCTION 145 I. SCIENCE AND LAW OF VARIANT RECLASSIFICATION 150 A. Scientific Background 150 1. Reclassification 150 2. Harms 157 B. Legal Background 162 1. Duties 162 a. Professional Negligence 163 b. Ordinary Negligence 170 2. Breach 172 3. Causation, Damages, and Defenses 174 II. IMPOSING GENETIC DUTIES 177 A. In Favor of Genetic Duties 177 1. Professional Ethics & Norms 178 2. Tort Theory 181 3. Tort Doctrines 186 B. Allocations Genetic Duties 187 1. Laboratories 189 2. Physicians 190 3. Patients 191 III. BREACHING GENETIC DUTIES 194 A. Going Forward 195 1. Proactive Measures 196 2. Technological Ease 198 B. Duty to Reinterpret 200 1. Boutique Lab 202 2. High-Volume Lab 203 C. Duty to Recontact 205 1. Clinical Geneticist 207 2. Oncologist 208 3. Family Doctor 210 CONCLUSION 211 INTRODUCTION

Imagine this scenario. A thirty-seven-year-old woman arrives at a medical center with stage 4 breast cancer. Despite a family medical history of breast and ovarian cancers, she was not getting additional cancer screenings. Why? Because the patient took a genetic test in 2010, and the results did not indicate an increased risk for BRCA1 /BRCA2 hereditary breast/ovarian cancer. (1) The patient, therefore, took no special precautions.

Following the breast cancer diagnosis in 2020, the patient sees a clinical geneticist. The clinical geneticist looks at the patient's pedigree and is puzzled. "This looks like a BRCA1 /BRCA2 family," she thinks, and decides to order another genetic test. The second time, the patient's BRCA1 test comes back positive for a heightened cancer risk. However, because the patient already has breast cancer, this newfound knowledge is of little help to her personally, (2) and she later dies. So what happened? And, more importantly, was her death preventable?

At first blush, it may seem incomprehensible that a patient could take a test for a BRCA1 mutation in 2010 and again in 2020 and get such different results. After all, our genetics do not generally change. (3) Much of our genome is determined before birth and--apart from the occasional random mutation here and there--largely stays the same throughout our lives. (4) How, then, can we explain our patient's experience? Did the original lab botch the test? Did the doctor give her another patient's results in 2010? Was she the victim of a rare environmental exposure that radically altered her DNA? The answer to all of these questions is no. The lab performed the test properly, the ordering physician gave her the right test results the first time, and her genetic sequence remained the same. Our understanding of genetics simply changed.

When scientists completed a rough draft of the human genome in 2000, it was only the beginning. (5) Although we had the genetic code, we did not--and indeed may never--fully appreciate its meaning. Researchers are constantly uncovering new genetic links and deepening our knowledge of how genetic variations impact our health. (6) Scientists make claims of new genetic discoveries, a new genetic link, or a newly discovered genetic function almost daily. (7)

Because so much of our genome is still a mystery, we may not fully understand the medical impact of a particular genetic variation. (8) We call those variations "variants of uncertain (or unknown) significance," or VUSs. (9) A VUS result reveals that the patient's genes differ from the majority of the population. (10) However, at the time of the testing, the science is not yet clear whether that difference is good, bad, or neutral. (11) Sometimes a genetic variation that we did not fully understand will take on new meaning. When a VUS gains clinical significance, it is no longer a VUS. (12) Based on this new knowledge, scientists can reclassify the variant from a VUS to benign, likely benign, likely pathogenic, or pathogenic. (13) A lab may then interpret the same genetic sequence differently depending on the scientific knowledge at the time of the testing. (14)

Such a scenario is what happened to our hypothetical patient. Around the time of her first genetic test in 2010, most research on BRCA1 genes had been done on women of predominantly European descent. (15) The science then was fairly good at detecting dangerous genetic variants in that population. (16) We did not, however, know as much about the genetics of breast cancer in people with non-European ancestry. (17) Imagine that our patient had genetic ancestors in sub-Saharan Africa. As a result, her BRCA1 variation came back as a VUS. Because the variant lacked known clinical significance, her doctor did not report the result as pathogenic. In the ensuing years, scientists began to study breast cancer in a wider range of patients. That research led the lab to reclassify the patient's genetic variant as likely pathogenic and, ultimately, as pathogenic in 2015. (18) When she took her second genetic test in 2020, her result was positive for a pathogenic variant. Had she known of this risk sooner, perhaps the patient could have caught the cancer at an earlier stage or even have had a prophylactic mastectomy, maybe saving her life.

At present, genetic testing laboratories and physicians have no recognized legal duties to take any action when a VUS gains clinical significance. (19) This Article considers the need for those genetic duties. Failing to inform patients of variant reclassifications can have life-or-death consequences. While we appreciate the gravity of this topic for patients, we also recognize the potential costs of these duties and the looming uncertainties regarding how the science and technology will develop.

Our proposal for imposing genetic duties has three parts: (1) proactive measures, (2) a legal duty to reinterpret, and (3) a legal duty to recontact. First, we encourage laboratories and physicians to act proactively by educating patients about the possibility of variant reclassification at the outset and by outlining the steps that the laboratories and physicians will (or perhaps will not) take to share the updated results. However, when that is not possible, we suggest that courts split the legal duties related to variant reclassification. Drawing from the concept of the cheapest cost avoider, we argue that labs are in the best position to reinterpret genetic test results, whereas ordering physicians are in the best position to recontact patients. Our liability framework would, therefore, impose the duty to reinterpret on the lab and the duty to recontact on the physician. Given the potential impact that legal liability could have on genetic testing and clinical care, we encourage courts to proceed with caution and to make these liability determinations on a case-by-case basis. Thus, while we advocate recognizing these duties, what constitutes a breach may vary significantly depending on the individual circumstances.

This Article is novel in at least two ways. One, it is among the first in the legal literature to address the need for potential legal duties related to variant reclassification. (20) Two, it proposes a solution to the cutting-edge question of how to fairly impose those potential duties. As such, it provides an important contribution to the conversation surrounding variant reclassification and can serve as a valuable resource for lawyers, medical professionals, judges, and scholars alike.

We discuss the legal implications of variant reclassification in three Parts. Part I gives the relevant scientific background and explores the existing tort doctrines likely to apply to variant reclassification. In Part II, we consider the arguments in favor of genetic duties related to variant reclassification, noting that laboratories are best situated to bear the costs of reinterpretation, while ordering physicians are best situated to bear the costs of recontacting patients. Part III proposes our framework for providing patients with access to updated test results. We begin by urging laboratories and physicians to take action now by developing policies to educate patients and to inform them of variant reclassifications. In older cases, when these proactive processes would not apply, we argue for bifurcating the duties associated with variant reclassification into (1) a duty to reinterpret and (2) a duty to recontact, and imposing those duties on their respective cheapest cost avoiders. We then analyze what would constitute a breach of these novel legal duties using a variety of case studies. We conclude that whether a defendant violated a genetic duty will depend heavily on the facts of the individual case.

1. SCIENCE AND LAW OF VARIANT RECLASSIFICATION

   Most of a person's genetic information is fixed before birth. (21) Yet, genetic test results--and the diagnoses of genetic conditions--can change over time, even while the content of the underlying genetic code remains exactly the same. (22) This somewhat counterintuitive reality is what lies at the heart of variant reclassification. This Part provides an overview of the science behind VUSs and explores the bodies of law that would apply to potential legal disputes relating to reclassifying variants.

   1. Scientific Background

      Here, we provide a brief explanation of exactly what VUSs are and how laboratories decide whether to reclassify them. We then turn to the harms that could occur when patients lack access to their updated results following a reclassification.

      1. Reclassification

         We can start with a review of high school biology. Our bodies are made up of cells. (23) The nuclei of our cells hold most of our DNA in the form of chromosomes. (24) Humans have twenty-three pairs of chromosomes, forty-six total, and those chromosomes contain our genes. (25) We have about twenty-four thousand genes. (26)

         Technically speaking, genes are molecules of deoxyribonucleic acid (DNA) that store genetic information as a series of base pairs. (27) Only four letters exist in the genetic "alphabet": adenine (A), cytosine (C)...