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Misuse of opportunistic screening highlights shortcomings in clinical ascertainment

Health Services and Implementation
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
The ACMG guidelines for returning medically-actionable secondary genomic variants have been implemented in many contexts including direct-to-consumer (DTC) genetic testing and in genomic research studies. These findings are considered “secondary” when obtained via non-clinical opportunistic screening pathways where there is no clear “primary” indication for sequencing. In many of these scenarios, if and how personal and family history data were obtained and to what extent these data were available to the entities responsible for ordering and/or interpreting sequence data is similarly unclear.  Like most participants in the literature describing outcomes of secondary findings (SF) receipt, most participants in our study of SF recipients are individuals who did not obtain their findings through clinical testing processes. We frequently encountered cases where even a minimally competent clinician should have recognized that diagnostic testing for the disorder detected should have been ordered.  It is widely recognized that the SF process is inappropriate for individuals who have an indication for testing (diagnostic testing). We set out to evaluate the degree to which secondary findings are being misapplied for diagnostic testing situations.

 

Methods:
We employed broad recruitment to enroll recipients of SF in a longitudinal study of health and behavioral outcomes of SF receipt.  In this study we collect as much genotypic, family history, and phenotypic data as practical and offer free cascade testing to relevant individuals until we can either identify an individual who harbored the SF genotype and was affected with the relevant phenotype, or we have exhausted the family for such candidates. We analyzed pedigrees from a subset of participants with SF in BRCA1/2 to examine the frequency with which these findings were returned as “secondary,” but should have been ascertained clinically based on pre-existing personal and family history data reported by participants. We applied NCCN criteria to these cases retrospectively to determine if they met current testing criteria.

 

Results:
Most of the 327 individuals we have enrolled to date received their findings through participation in research studies (n=200; 61%) or DTC testing (n=42; 13%). Eleven percent of participants were directly referred to our study by a clinician (n=10) or through partnership with a clinical testing laboratory (n=25). We completed data collection for 292 of these individuals and 87 of these had SF in BRCA1/2. Of these, 40 (46%) met NCCN criteria for consideration of diagnostic testing for a hereditary cancer syndrome. The most frequent reasons for meeting criteria included personal (n=3) or family history of early-onset breast cancer in a first- (n=7) or second-degree (n=16) relative and ovarian cancer in a second-degree relative (n=9).

 

Conclusion:
The high fraction of participants with BRCA1/2 SF with recognizable personal/family histories that should have prompted diagnostic testing we report here supports the notion that clinical genetic testing is underused. While opportunistic screening is not a substitute for diagnostic testing, it provides an important mechanism to inform individuals and families of serious disease risks. Because ACMG recommendations only endorse the return of pathogenic and likely pathogenic variants, many sequenced individuals and families evaluated for SF through clinical or adapted pipelines may harbor high VUS variants that are not returned. These individuals and families will suffer from not receiving the evaluation and risk management care that they would have received were they to have gotten appropriate testing in a diagnostic, rather than opportunistic setting.

 

Agenda

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