By Diagnostics World Staff
July 17, 2017 | In an invited commentary published on Friday in Genetics in Medicine, Heidi Rehm outlines the state of variant interpretation, and makes a call to the community to share variant interpretation data. “I… put out a plea to the community to step up and take action to ensure transparency in variant interpretation, to allow laboratories to subject their interpretations to peer review by the community, and to enable aggregation of evidence to improve knowledge over time,” Rehm writes. (doi:10.1038/gim.2017.90)
In the past five years, variant interpretation has changed dramatically. Standardization has come through guidelines like those from ACMG-AMP, and through a “share and compare” approach between laboratories. “When laboratories began sharing data in ClinVar, the differences in variant interpretation methods that had been used over the past ten years became clear,” Rehm writes. “For some variants, the aggregate evidence from multiple laboratories moved variants from a classification of uncertain to either pathogenic or benign.”
The variety of variant interpretations within ClinVar has not escaped notice—Rehm acknowledges critiques from Gradishar et al. and Vail et al.—but she argues that ClinVar’s growth speaks for itself, and that differences within the database are often easily reconciled.
In the same issue of Genetics in Medicine, Rehm’s own lab reconciled differences between interpretations submitted by four clinical laboratories—Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory. Participating laboratories increased their overall concordance from 88.3% to 91.7%, mostly by reassessment with current ACMG-AMP criteria and internal data sharing. (doi: 0.1038/gim.2017.14)
In fact, in Rehm’s own experience—admittedly biased toward ClinVar and ClinGen—she sees “a strong correlation between the quality of interpretations and whether the laboratory is a ClinVar submitter,” she says. “I have also personally watched laboratories dramatically improve their interpretation methods after engaging in active data sharing in ClinVar.”
Rehm calls various stakeholders in the community to demand increased variant data sharing through ClinVar. She asks that the College of American Pathologists, which accredits most genetic testing laboratories, to make submission to ClinVar a requirement of quality assurance. She asks journal editors and individual reviewers to make ClinVar submission a requirement for publication.
She encourages payers to only reimburse tests from laboratories that participate in transparent data sharing, and asks health care providers to only order from labs that share data. ClinGen published a list of the clinical laboratories that meet minimum requirements for data sharing. Only ten labs are listed, and only three—GeneDx, Invitae, and Partners Laboratory for Molecular Medicine—meet the minimum requirements plus the additional achievements that ClinGen tracks.
The end goal of variant interpretation is better patient care, Rehm says. Medicine is not an exact science, and Rehm doesn’t expect variant interpretation to ever be completely concordant. “Nevertheless,” Rehm says, “we must ensure that the professional opinion of geneticists is based on a fully shared body of evidence with open and ongoing community review, and that we support this endeavor in a cost- effective manner... It is time we considered the sharing of variant interpretations a fundamental right of patients to ensure that they receive accurate clinical care."