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At NSGC, Genetic Counselors Discuss Why, How Gene Variants Are Reclassified

ATLANTA (GenomeWeb) – Just what a genetic variant may mean for a clinical diagnosis isn't always clear and can change over time, according to speakers at the National Society of Genetic Counselors annual meeting, held here last week.

"Variant interpretation is a work in progress," Karen Wain, a genetic counselor at Geisinger Medical Center,  said during a session on variant interpretation.

Some variant reclassifications may arise simply because the field is moving rapidly and new studies are continually added to the literature, bolstering evidence that a gene or variant is associated with a disease or that it is not. Other reclassifications may come as more is learned about patients' families and the association there between a variant and disease.

Zoe Powis, a senior clinical research specialist at Ambry Genetics, and her colleagues examined how often and why genes and variants identified through exome sequencing underwent later reclassification.

Of the 7,719 exome-sequencing cases they analyzed, 636 underwent reanalysis, and a portion more than once. This reanalysis was sometimes initiated by the lab and sometimes by the healthcare provider. For the 256 lab-initiated reanalyses, 82 percent of the cases analyzed had an upgrade in severity and 15 percent had a downgrade, while for the 417 provider-initiated cases, reanalysis typically led to neutral changes.

Most often, the reason for a reclassification of a gene was due to new findings reported in the literature, while variant reclassification was often due to family studies.

Powis said it's important for genetic counselors to know whether their labs initiate reevaluations on their own. "Proactive reanalysis is really important for patients," she said, as it can lead to changes in patient management.

When asked by an audience member how often a genetic counselor should seek reanalysis, Powis said it was hard to say, as is depends on what is being reported in the literature. She added, though, that many genetic counselors ask for such reevaluation when patients return for follow-up sessions

Family studies can also inform whether a variant is pathogenic or not.

But Ginger Tsai, a genetic counselor at the University of Washington, said that previous work had found limited uptake of family studies, as an average 0.5 family members were reported to be genotyped per proband. She and her colleagues sought to boost that number and determine more concrete classifications for VUS using a patient-driven model.

In this approach, patients contacts them — after hearing about the study by word of mouth, patient forums, or from staff — with their VUS that they want to figure out and are directed to a website called that discusses what a family study is.

Tsai and her team then examine the patients' VUS on a pedigree and annotate them, and that initial patient-family member point person then recruits relatives to join the family study. Tsai noted that relative recruitment was an iterative process, which allowed them to then focus on, for instance, the paternal side if that was where the variant was present.

Most of the variants investigated were in BRCA1, BRCA2, or Lynch syndrome genes, she said, though noted it was open to all VUS. In all, they did this analysis for 92 families, which led to the reclassification of 56 VUS. Most — 70 percent — were reclassified as likely benign, 11 percent as benign, 9 percent as likely pathogenic, and 11 percent as pathogenic. Reclassifications took a median 298 days.

Tsai and her colleagues reported some of these results late last month in Genetics in Medicine.

Such a family study was able to reclassify as benign a VUS in BRCA2 identified in a woman whose mother had had ovarian cancer after the proband recruited numerous family members via social media, Tsai said.

For a subset of their cohort that had been enrolled in the study for more than a year, Tsai and her colleagues found that they genotyped 4.5 relatives per proband — eight times more than that previous study.

This, she said, gives the opportunity to genotype affected and unaffected family members to speed up the reclassification process, while also allowing patients to actively contribute to research and their own care.