Abstract P6-08-15: Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center
Authors: Simon Michael Steven , Abdallah Nadline , Assad Hadeel , Reagle Rachel , Petrucelli Nancie , Purrington Kristen 
Published: March 2020

Abstract
Background It is estimated that up to 10% of women diagnosed with breast cancer in the United States have a BRCA1 or BRCA2 inherited susceptibility, which accounts for approximately 125,000 women. There are racial and ethnic differences in the prevalence and types of pathogenic mutations and variants of uncertain significance (VUS) in BRCA1 and BRCA2. To better understand the prevalence of recurring pathogenic mutations and/or uncover novel mutations in specific racial and ethnic groups, we evaluated the mutational profile of individuals who had genetic counseling and testing at a large urban NCI designated Comprehensive Cancer Center. Methods Data was extracted from the Karmanos Cancer Institute (KCI) Cancer Genetic Counseling Service database over a 19 year period through 12/31/18. The cohort consisted of 5,929 individuals evaluated for high-risk of hereditary disease at 6 sites across Michigan including Detroit. We estimated the prevalence of BRCA1/2 pathogenic mutations and variants of uncertain significance (VUS) by race and ethnicity. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to compare the rate of pathogenic and VUS mutations in race and ethnic groups with non-Hispanic whites (NHW) indicated as the reference group. Results There were 3,114 (52.5%) unrelated individuals who underwent clinical BRCA1/2 testing. The racial/ethnic breakdown of the cohort included: 68.4% NHW, 21% African American (AA), 2.7% Ashkenazi Jewish (AJ), 2.2% Arab, 0.9% Hispanic (H), and 4.8% other. There were 290 individuals with pathogenic mutations (137 BRCA1 and 153 BRCA2) and 186 with VUS (61 BRCA1 and 125 BRCA2). For BRCA1, there were no differences by race and ethnicity in pathogenic mutations, however AA and Arab individuals were more likely to have VUS compared to NHW (OR & 95% CI, 2.63, 1.53-4.54 and 3.39, 1.01-11.41) respectively. For BRCA2, AJ individuals were more likely to have pathogenic mutations compared to NHW (OR & 95% CI, 2.51, 1.22-5.17) and both AA and AJ individuals were more likely to have VUS (OR & 95% CI, 1.55, 1.02-2.35 and 3.15, 95% CI 1.46-6.79) respectively. The table lists the most common pathogenic mutations seen in BRCA1 and BRCA2 by race and ethnicity. All mutations are unique and seen in more than one person unless indicated. Conclusions AA, Arab and AJ individuals were more likely to have VUS in BRCA1&BRCA2 than NHW suggesting the importance of variant reclassification in understanding cancer risk in racial and ethnic minority groups. Understanding the prevalence of BRCA1/2 mutations in specific racial and ethnic groups can potentially lead to customization of genetic testing and possible classification of new founder mutations.
The most common pathogenic mutations by race and ethnicityRace/EthnicityBRCA1 (n)BRCA2 (n)% of Total MutationsNHWp.Glu1756Pro (14)p.Ile605Asn (7)p.Cys61Glu (5)p.Arg645Glu (2)p.Ser1253Arg (4)p.Ala938Pro (2)BRCA1: 28/102=27.5%p.Lys894Thr (3)p.Glu2198Asn (2)BRCA2: 17/103=16.5%p.Asp825Glu (2)2)p.Gln1886Ter (2)p.Asn312Ile (2)AA5296del4 (2)p.Gly1013Glu (2)IVS16+6T&gt;C (2)p.Lys2496Ter (2)BRCA1: 6/23=26.1%p.Thr276Ala (2)p.Lys936Asn (2)BRCA2: 8/32=25%p.Lys1872Asn (2)AJp.Glu23Val (1)p.Ser1982Arg (5)BRCA1: 1/1=100%BRCA2: 5/9=55.6%Arabp.Gln12X(1)p.Ile1859Lys (2)BRCA1: 1/5=20%BRCA2: 2/3 = 66.7%Hispanicp.Arg71Gly (1)p.Glu1308Ter (1)BRCA1: 1/1=100%BRCA2: 1/1=100%
Citation Format: Michael Steven Simon, Nadline Abdallah, Hadeel Assad, Rachel Reagle, Nancie Petrucelli, Kristen Purrington. Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-15.