Discrepancies between tumor genomic profiling and germline genetic testing

Background: Tumor genomic profiling (TGP) often incidentally identifies germline pathogenic variants (PVs) associated with cancer predisposition syndromes. Methods used by somatic testing laboratories, including germline analysis, differ from designated germline laboratories that have optimized the identification of germline PVs. This study evaluated discrepancies between somatic and germline testing results, and their impact on patients. Patients and methods: Chart reviews were carried out at a single institution for patients who had both somatic and designated germline genetic testing. Cases with discrepant results in which germline PVs were not detected by the somatic laboratory or in which variant classification differed are summarized. Results: TGP was carried out on 2811 cancer patients, 600 of whom also underwent designated germline genetic testing. Germline PVs were identified for 109 individuals. Discrepancies between germline genetic testing and tumor profiling reports were identified in 20 cases, including 14 PVs identified by designated germline genetic testing laboratories that were not reported by somatic testing laboratories and six variants with discrepant classifications between the designated germline and somatic testing laboratories. Three PVs identified by designated germline laboratories are targets for poly adenosine diphosphate-ribose polymerase (PARP) inhibitors and resulted in different treatment options. Of the PVs identified by designated germline laboratories, 60% (n = 12) were in genes with established associations to the patients' cancer, and 40% of the PVs were incidental. The majority (90%) of all discrepant findings, both contributory and incidental, changed management recommendations for these patients, highlighting the importance of comprehensive germline assessment. Conclusions: Methods used by somatic laboratories, regardless of the inclusion of germline analysis, differ from those of designated germline laboratories for identifying germline PVs. Unrecognized germline PVs may harm patients by missing hereditary syndromes and targeted therapy opportunities (e.g. anti-programmed cell death protein 1 immunotherapy, PARP inhibitors). Clinicians should refer patients who meet the criteria for genetic evaluation regardless of somatic testing outcomes.

Automated summary

This study evaluated discrepancies between tumor genomic profiling and germline genetic testing, and found that unrecognized germline pathogenic variants may harm patients by missing hereditary syndromes and targeted therapy opportunities. The findings highlight the importance of comprehensive germline assessment and referring patients for genetic evaluation regardless of somatic testing outcomes.