Abstract P4-05-06: Elevated frequency of a deleterious deep intronic BRCA2 splice variant in non-Caucasian Americans
Authors: Strom Charles M , Rivera S , Peng M , Conlon Wendy , Crossley B , Sun W 
Published: May 2015

Introduction: In 2012, Anczukow et al (Clin Cancer Res 2012;18:4903-9) described a deep intronic BRCA2 variant between exons 12 and 13 that was discovered because a cell line from a patient with hereditary breast and ovarian cancer (HBOC) produced an aberrant mRNA. The variant (c.6937 +594 T&gt;G; rs191253965), which further improved splice site sequence to consensus, was also identified in 8 additional families. Segregation analysis of 13 affected relatives from 6 families revealed that all affected family members had the c.6937 + 594 T&gt;G variant, providing strong evidence that it is deleterious. All resided in France, but ethnicity was not specified. This variant was also seen in 5 individuals in the 1000 genomes project. Since this is a deep intronic variant, standard BRCA2 sequencing tests that determine only a limited number of bases into each intron would not detect it. For these reasons, we included a bait tile for the intron harboring this variant in the design of our hybrid capture-based next generation sequencing (NGS) test for comprehensive BRCA1 and BRCA2 analysis. Here we investigate the frequency of this variant in samples submitted for comprehensive BRCA1 and BRCA2 testing, and assessed carrier frequency in samples submitted for non-BRCA–related genetic testing.

Methods: We reviewed the de-identified results of the first 2300 clinical samples submitted to our reference laboratory for comprehensive BRCA1 and BRCA2 testing to assess the frequency of the c.6937 + 594 T&gt;G variant.

Results: This deep intronic variant was observed in 12 of the initial 2300 patient samples. All 12 individuals were affected with HBOC and were Hispanic. To estimate the population frequencies of this variant in various ethnic groups, we anonymized samples submitted for Cystic Fibrosis Carrier Detection and subjected them to a single-site assay for this variant. In all, 344 patients self-identified as Caucasian, 355 as Hispanic, 140 as African American, and 73 as Asian. The frequency of c.6937 +594 T&gt;G heterozygotes was 0.30% (1 individual) in Caucasians, 1.1% (4) in Hispanics, 0.8% (1) in African Americans, and 1.4% (1) in Asians.

Conclusions: In an initial series of comprehensive BRCA analyses, we discovered that a deep intronic variant known to cause aberrant splicing and to segregate with HBOC is present at elevated frequencies in non-Caucasian Americans. We have already observed this variant in 12 Hispanic HBOC patients. Physicians could consider testing for this variant in women of non-Caucasian ancestry with HBOC who have had negative results on BRCA assays that do not test for c.6937 +594 T&gt;G.

Citation Format: Charles M Strom, S Rivera, M Peng, Wendy Conlon, B Crossley, W Sun. Elevated frequency of a deleterious deep intronic BRCA2 splice variant in non-Caucasian Americans [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 P4-05-06.