Variant Reclassifications In Hereditary Cancer Genetics And Their Implications For Clinical Care

BACKGROUND: Clinicians who provide genetic cancer risk assessment (GCRA) are dependent on laboratory reporting of germline results to inform cancer screening and treatment recommendations. Efforts to enhance variant classification and harmonization, such as ClinVar, will lead to an increase in the number of variants being reclassified. Given that the impact of variant reclassification on care is unknown, we evaluated the frequency and clinical impact of variant reclassification on individuals seen for GCRA. METHODS: We retrospectively evaluated data on 7,356 participants enrolled through the Clinical Cancer Genomics Community Research Network (CCGCRN) at City of Hope and Olive View Medical Center from September 1996- October 2016. RESULTS: 4,969 commercial genetic tests yielded a total of 1,610 variants of any category, of which 181 unique variants in 20 genes were reclassified. BRCA1 and BRCA2 (BRCA) and mismatch repair genes comprised 73.5% and 5.5% of the genes reclassified, respectively. Reclassification impacted 225 individuals (97% women) from 217 families; 89% of these individuals (n=201) had a personal history of cancer. The interval between initial report and variant reclassification averaged 3 years (17 days- 13 years). Minorities had higher reclassification rates as compared to non-Hispanic white participants (P = 0.0149). Of the 181 unique reclassifications, 164 (90.6%) of variants were downgraded. Sixteen reclassifications led to changes in clinical care. Thirteen variants carried by 15 individuals were upgraded from a variant of uncertain significance (VUS) to likely pathogenic or pathogenic (10 BRCA, 3 MLH1 or MSH2). These reclassifications prompted additional prophylactic surgical interventions (i.e., bilateral salpingo-oophorectomy), specialist referrals, and surveillance recommendations for at risk patients and family members. Three variants (NBN p.Arg215Trp, PTEN p.Ala79Thr, and MET c.1200+2Tu003eC) were downgraded from likely pathogenic or pathogenic to VUS. Prior to downgrade to VUS, 2 cases had unnecessary surveillance procedures. CONCLUSIONS: Since many genomic variants will be reclassified over time, it is critical that laboratories deliver prompt notification of reclassifications, and that providers involved in GCRA discuss the possibility of variant reclassification with patients and family members and collect patient/proxy information during informed consent so that re-contact is possible. Given the non-trivial effort required for variant reclassification and patient/participant re-contact, system-level interventions are needed to facilitate genomic reinterpretation and the return of results to individuals over time. Citation Format: Thomas P. Slavin, Stacy W. Gray, Lily R. Van Tongeren, Ilana Solomon, Christina Rybak, Bita Nehoray, Lili Kuzmich, Mariana Niell-Swiller, Kathleen R. Blazer, Kai Yang, Julie Culver, Sharon Sand, Danielle Castillo, Josef Herzog, Jeffrey N. Weitzel. Variant reclassifications in hereditary cancer genetics and their implications for clinical care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2017-4273