Discrepancies between germline and somatic laboratories in the reporting of germline cancer predisposition variants.

Abstract

10568 Background: Individuals with a cancer diagnosis may not qualify for germline testing to identify cancer predisposition variants due to restrictive testing guidelines. However, many have somatic Next Generation Sequencing (NGS) to guide treatment. Somatic NGS may offer a less restrictive approach to identify germline variant carriers. However, the rate of germline variant reporting via somatic NGS is unclear. We investigated what percentage of known germline variants were reported by matched somatic testing laboratories. Methods: Cancer patients seen at Rutgers Cancer Institute who had a positive germline report between 1/1/18 and 1/31/23 and at least one matched somatic NGS report on file were eligible for the study. We compared each germline-somatic report pair to analyze if the pathogenic/ likely pathogenic (P/ LP) germline variant was reported by the somatic NGS laboratory. We also assessed factors impacting germline variant reporting. Results: A total of 65 cases were included. Of matched somatic reports, 52.9% reported the corresponding germline variant, while 47.1% of germline variants were not reported by the matched somatic laboratory. The most frequent reasons germline variants were not reported included: (1) the gene was not included on the somatic NGS panel (60%), (2) the germline variant was filtered out of reporting by the somatic NGS laboratory as a suspected incidental germline finding of limited treatment relevance (10%), (3) the variant was intronic (7.5%), and (4) the variant was a copy number variant (7.5%). Less common reasons germline variants were not reported included differences in variant interpretation, limited coverage in the region containing the variant, and suspected mosaicism and/or clonal hematopoiesis. Conclusions: Almost 50% of germline variants in this cohort were not reported by the corresponding somatic laboratory. So, our findings suggest that clinical providers cannot rely on somatic NGS for germline variant reporting. We also expanded on reasons certain germline variants were not reported by somatic laboratories beyond reasons previously reported. In our cohort, the second most common reason germline variants were not reported was because the variant was detected and then intentionally filtered out of reporting. In these cases, the somatic lab interpreted the variant as an incidental finding of probable germline origin with limited treatment relevance. This highlights the different goals of germline vs somatic testing labs and how these varying goals impact what is reported to ordering clinicians. We hope our findings will contribute to the growing literature surrounding the overlap between germline and somatic testing methodologies and assist clinicians in their interpretation of genomic results.