An article recently published in Nature discusses a legal case in which a #cardiology#genemutation classification has been evaluated by 2 expert groups. The stakes of an accurate classification are high since they impact the freedom or continued incarceration of a mother for allegedly killing her four children. She has already served 20 years in prison for the deaths. Instead of murder, a #gene variation in calmodulin2 (CALM2) may have been the cause of the deaths, but the 2 expert groups disagree on the clinical classification of the CALM2 genetic variant.

“The disagreement between the two teams partly reflects the modern history of clinical genetics. The rapid pace of genomics research over the past two decades powered an exuberant search for pathogenic mutations. The medical literature is littered with papers that claimed to have identified dangerous gene variants that later turned out to be harmless. “It became a bit of a wild west,” says Hugh Watkins, a cardiologist at the University of Oxford, UK, who studies genes that cause sudden cardiac death.”

‘Disagreements’ on how variations are classified is a consistent issue within #genetics today. While reliability of genetic variant detection is something that has not been mastered yet by some clinical labs, an even larger issue is HOW detected genetic variants are clinically classified by labs. Clinical classifications of variants made by labs often determine what surgeries or drugs patients receive. Variant classification archives such as #ClinVar aren’t always accurate – since garbage in results in garbage out. For some labs with low evidence requirements for variant classification, a published case study or small evaluation of 1 or 2 patients gives enough ‘evidence’ for a lab to issue a positive result. This could be a FALSE positive, while a more careful lab would keep the variant classified as uncertain until addt’l evidence clarifies the variant’s classification.

This article shows that 2 teams of experts cannot always come to agreement when brought together to evaluate the clinical classification of a single genetic variation. Yet imperfect clinical classifications, under the aspirational branding of #PrecisionMedicine, occur in labs globally, everyday for thousands of patients. When #DNA is sent to a lab, it is analyzed by scientists & put into the labs’ bioinformatics to push out a result, oftentimes being signed off by a medical director that doesn’t closely inspect the evidence for variant classification. #Patient care (or innocence in this case) is determined by these results. When teams of experts can’t even come to a consensus in a high profile high stakes case, how do regular patients and #clinicians know that the lab they’re getting results from is both correctly IDENTIFYING and carefully CLASSIFYING genetic alterations accurately?

It’s a lot to think about. Our nonprofit, the Center for Genomic Interpretation, thinks and works on this problem every moment of every day.

Read full article HERE.