Abstract P4-12-05: Individuals with more than one pathogenic variant: Rationale for considering multi-gene panel testing for cancer susceptibility
Authors: Nusbaum Rachel , Susswein Lisa , Hruska Kathleen , Hussong Melanie , Berkofsky-Fessler Windy , Liao Mingjuan , Rinella Erica , Sanapareddy Nina , Villar Joaquin , Wan Haiyan , Xu Zhixiong , Bassett Rebecca Y , McKeen Elisabeth , Murphy Constance , Pencarinha Deborah , Booker Jessica , Cremona Maria L , Murphy Patricia , Klein Rachel T 
Published: May 2015

Introduction: Expansion of genetic testing technologies has brought multi-gene panels for cancer susceptibility into the clinic; however, the clinical utility of these next-generation sequencing (NGS) panels is largely unknown.

Hypothesis: We hypothesized that the use of multi-gene panels would yield a significant number of cases with more than one pathogenic variant.

Methods: We retrospectively queried oncology tests reported at GeneDx from August 2013 to April 2014 for individuals with more than one pathogenic variant. Next, we calculated the proportion of individuals with more than one pathogenic variant among all positive reports, excluding familial and stand-alone BRCA1/2 tests. We then extracted personal and family histories, including available segregation data, to categorize the phenotypes.

Results: Of 406 unique, unrelated individuals with pathogenic or likely pathogenic findings, 11 (2.7%) had more than one pathogenic variant. This total includes nine individuals with a mutation in more than one gene, as well as two individuals with two mutations in trans in the same gene. Ten of these 11 individuals were identified by multi-gene panel tests, one individual by step-wise (tiered) testing. Seven of 11 individuals were positive for a pathogenic variant in a traditional, highly-penetrant cancer susceptibility gene and another pathogenic variant in a gene with moderate cancer susceptibility, such as CHEK2 and ATM. Three of 11 probands had more than one primary tumor. Several of the families were significant for bilineal cancer risk.

Conclusions: Our data suggest that a traditional single gene approach to cancer testing may fail to identify all pathogenic variants related to the clinical presentation. The identification of a second risk factor for inherited susceptibility to cancer allows for appropriate testing and management considerations for family members. In conclusion, we provide early evidence for the consideration of multi-gene panel testing in a clinical oncology setting.

Citation Format: Rachel Nusbaum, Lisa Susswein, Kathleen Hruska, Melanie Hussong, Windy Berkofsky-Fessler, Mingjuan Liao, Erica Rinella, Nina Sanapareddy, Joaquin Villar, Haiyan Wan, Zhixiong Xu, Rebecca Y Bassett, Elisabeth McKeen, Constance Murphy, Deborah Pencarinha, Jessica Booker, Maria L Cremona, Patricia Murphy, Rachel T Klein. Individuals with more than one pathogenic variant: Rationale for considering multi-gene panel testing for cancer susceptibility [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-05.