Abstract
SNaPshot next generation sequencing (NGS) tumor genotyping is used to guide clinical decision-making in the diagnosis, prognosis and treatment of cancer patients at Massachusetts General Hospital. Analysis focuses on somatic alterations in tumor tissue; however, variants of suspected germline origin may be incidentally identified. Our study examined how frequently suspected germline variants (SGVs) were detected for non-lung cancer patients who underwent SNaPshot NGS between December 1, 2014 and May 31, 2015. We selected cases with at least 1 variant present at an allelic fraction between 42-58% in a gene associated with a hereditary cancer syndrome in order to identify cases likely to have SGVs warranting genetic counseling referral. We used ClinVar, COSMIC and ExAC to assess the clinical germline significance for each SGV. Thirty-eight of 599 patients (6.3%) had at least one deleterious SGV of potential clinical germline significance; 98 patients had SGVs that were deemed to have low potential for clinical germline significance. Report annotation indicating suspected germline origin was present for 19.5% of deleterious SGVs of potential clinical germline significance, and for 32.5% of SGVs of low potential for clinical germline significance. We determined risk for hereditary cancer syndromes by considering SGV assessment and concordance with personal and/or family history; 11 patients were considered to be at high or moderate risk for a hereditary cancer syndrome. We did not find evidence of genetic counseling referrals made based on SGVs in the timeframe of our study. Our data show that SGVs of clinical significance for hereditary cancer syndromes may be detected through SNaPshot NGS tumor genotyping, and highlight the challenges in the reporting of and genetic counseling follow-up for SGVs. A multi-disciplinary effort involving medical oncology, genetics and molecular pathology practices may be an optimal approach to identifying patients at high risk for a hereditary cancer susceptibility.