ATLANTA (GenomeWeb) – Clinical variant interpretation does not end once a lab report is issued as genetic counselors and others sometimes re-interpret the results, according to speakers at the National Society of Genetic Counselors' annual meeting.
Prior to the establishment of guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, clinical variant interpretation at labs was a bit of the "Wild West," according to Carol Saunders, clinical director at the Center for Pediatric Genomic Medicine at Children's Mercy Hospital, who spoke at a session. As a result, variant interpretation between clinical labs was up to 60 percent discordant, she said.
"It is a very subjective process," Saunders said, that is becoming more evident as ClinVar submissions increase and as more labs have analyzed the same variants.
ACMG/AMP guidelines introduced different types and strength levels of evidence that could be used to support calling a variant as pathogenic, likely pathogenic, likely benign, benign, or of uncertain significance. Now, about 97 percent of surveyed labs use those evidence criteria.
However, according to Emily Farrow, an associate professor of pediatrics at the University of Missouri-Kansas City School of Medicine, there are no guidelines for what happens after a clinical lab report is issued, and how a genetic counselor returns results can vary widely. She added that a survey recently presented at the American Society of Human Genetic annual meeting found that about 68 percent of genetic counselors performed some of their own interpretations for reported variants.
"Getting it wrong can cause patients harm," Farrow noted.
She and her colleagues conducted a study of clinicians who had provided genetic testing results to patients, combining survey data, interviews, and retrospective chart reviews. For pathogenic results, they found that slightly more than half the clinicians always or frequently conducted additional research, and for VUS, a little less than half did. More than half, though, always or frequently conducted additional research on likely pathogenic variants.
Their reasons for doing so varied: some wanted to educate themselves, while others were investigating the interpretation, often to see if it fit the patient in question.
Farrow and her colleagues also found that clinicians might describe a variant's significance differently from what is on the lab report. Some may, for instance, play up a VUS and its link to disease, while others may downplay it because of the uncertainty. Part of what influenced clinicians to do their own analysis was their level of trust in the lab providing the results, she said.
The session chair, Courtney Berrios, a genetic counselor at Children's Mercy, also polled the session audience via a web app. About half of those who took the poll said they seek additional information frequently. In particular, about half said they always did so for a VUS, while about 30 percent said they always did for a likely pathogenic variant, and between 20 percent and 25 percent said they did this for a pathogenic variant.
In her chart review, Farrow and her team found that of 37 cases in which genetic tests were ordered by non-genetic specialists, four non-diagnostic results were re-interpreted by the clinical team as diagnostic, while two diagnostic lab results were reinterpreted by the clinical team as non-diagnostic. These reinterpretations, they found, led to three changes in treatment recommendations, two screening tests, and six estimates of recurrence risk.
"We are having an impact clinically," Farrow said.
Saunders also described a case in which a VUS warranted further investigation. A nine-year-old boy was admitted to the pediatric intensive care unit with a nasty rash, vomiting, and abdominal pain. He had a history of prior hospitalizations as well as normal development and intellect and was referred for next-generation sequencing with a suspicion of an immunodeficiency.
The analysis found he was homozygous for a VUS in the gene HLCS, which is associated with holocarboxylase synthetase deficiency. Saunders noted that the boy's symptoms didn't fit with the classical presentation of the conditions, but that the clinical team decided it was prudent to rule it out biochemically, especially as it is a treatable condition. That test instead confirmed the condition, and the biochemical evidence bumped the variant up from a VUS to a pathogenic variant.
Farrow noted that what is included in a lab report is also subjective. For example, this VUS was likely included because the boy had a rash. There is clinical judgment involved in what should or should not be listed, she said.