Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making.

OBJECTIVE: Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations. METHODS: Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist. RESULTS: We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%). CONCLUSIONS: Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients.

Scaling resolution of variant classification differences in ClinVar between 41 clinical laboratories through an outlier approach.

ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar submissions from 41 clinical laboratories to detect variants with MSDs between the laboratories (650 variants). Next, MSDs were filtered for variants with ≥3 classifications (244 variants), of which 87.6% (213 variants) had a majority consensus in ClinVar, thus allowing for identification of outlier classifications in need of reassessment. Laboratories with outlier classifications were sent a custom report and encouraged to reassess variants. Results were returned for 204 (96%) variants, of which 62.3% (127) were resolved. Of those 127, 64.6% (82) were resolved due to reassessment prompted by this study and 35.4% (45) resolved by a previously completed reassessment. This study demonstrates a scalable approach to classification resolution and capitalizes on the value of data sharing within ClinVar. These activities will help the community move toward more consistent variant classifications, which will improve the care of patients with, or at risk for, genetic disorders.