The identification of genetic variants of uncertain significance is a fairly common, albeit unwelcomed result of gene sequence analyses. The frequency at which these variants are identified will likely continue to increase with the introduction of next-generation sequencing panels and the recent availability of clinical exome sequencing. When applied to testing for cancer predisposition syndromes, accurate variant assessment and classification helps to guide screening, treatment, family planning, and testing of at-risk family members. Multiple resources are available to assess genetic variants: population-based cohort allele frequencies, published literature, in silico prediction tools, gene-specific databases, evolutionary conservation data, and co-segregation studies. Ambry Genetics, a CAP-accredited and CLIA-certified commercial clinical laboratory providing genetic services focused on clinical diagnostics and genomic services, has developed and implemented a complementary family studies program to collect co-segregation data for variants of unknown significance identified through diagnostic testing. The Ambry family studies program is available to all specialties, but is especially active for genes associated with cancer predisposition and intellectual disability. Data collected from the cancer family studies program is combined with published literature, database information, and data compiled with Ambry Variant Analyzer (AVA©), a novel bioinformatics tool, to allow for a comprehensive interpretation of all variants of uncertain clinical significance in cancer predisposition genes. In less than one year, the program has grown to 60 active cancer family studies at the time of submission and a current rate of >5 new applications per week. Variants successfully reclassified due to family studies data include the p.Y327D missense alteration in MEN1 and in-frame deletions in both TP53 and MLH1. Variant reclassification leads to the automatic generation of amended reports for any individual previously identified by our laboratory as a carrier. Immediately distributed to health care professionals, these reports offer the most up-to-date clinical interpretation possible improving medical decision making and clarifying risk of disease. Here we provide an overview of the family studies program and discuss successful variant reclassification via the Ambry model.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2096. doi:1538-7445.AM2012-2096