Tatineni, Sushma

Abstract Purpose: The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period. Methods: The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group. Results: The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and <1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58).Conclusion: These results suggest the continued need for genetic testing and variant reclassification for individuals of all race and ethnic groups.

AbstractBackgroundThere is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer.MethodsWe evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non‐Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry.ResultsThe racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24–0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18–1.98, p = 0.001 and OR 95% CI, 2.28, 1.17–4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial).ConclusionsUnderstanding the racial and ethnic distribution of pathogenic variants in multi‐gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer.

e13540 Background: The identification of pathogenic variants and variants of unknown significance (VUS) in multi-gene cancer predisposition testing raises new questions regarding cancer risk and management. We evaluated the personal and family cancer patterns and variation by race and ethnicity, among individuals positive for pathogenic variants in non-BRCA1/ 2 cancer predisposing genes. Methods: The Karmanos Cancer Institute (KCI) Cancer Genetics database was queried from May 13, 2013 through December 31, 2018. There were 3,544 unrelated individuals evaluated for hereditary cancer predisposition of whom 1,868 had 18-gene panel testing at 6 sites across Michigan. Data was collected on personal and family cancer history including ages at diagnosis utilizing a 3-generation pedigree, self-identified race and ethnicity and results of genetic testing. We describe the prevalence of pathogenic variants by proband cancer diagnosis, family history, race, and ethnicity. Results: The race/ethnic distribution of the tested cohort included 67.5% non-Hispanic White (NHW), 24.4% African American (AA), 2.1% Arab, 1.8% Ashkenazi Jewish (AJ), 1.0% Hispanic, and 3.4% other. The distribution of cancer diagnoses included 40.6% breast, 5.5% ovarian, 4.1% colon, 3.5% endometrial, 2.0% pancreas and 39.7% unaffected. Pathogenic variants were seen in 151 (8.1%) individuals and VUS in 309 (16.5%). The five most common pathogenic variants were CHEK2 (40), MUTYH (22), ATM (20), and PALB2 (18). The most common pathogenic variants by race and ethnicity were CHEK2 (NHW), RAD51C (AA), PALB2 (Arab), CHEK2, MSH6 (AJ), and none in Hispanics. Variants associated with the four most common cancer types were breast ( CHEK2 ), ovarian ( CHEK2, MUTYH, BRIP1), colon ( ATM), and endometrial ( MSH6, PALB2). Of 40 individuals with CHEK2 variants, 92.5% were NHW, and 34 (85%), 31 (78%), 10 (25%), 1 (2.5%) had family history of breast cancer, breast cancer before age 50, ovarian, and colon cancer, respectively. Of 20 with ATM variants, 95% were NHW, 13 had family history data and 10 (76.9%), 8 (61.5%), 2 (15.4%), 1 (7.7%) had family history of breast, breast cancer before age 50, ovarian, and colon cancer, respectively. Conclusions: Pathogenic variants seen using multigene panel testing differ by race, ethnicity and personal/family history of cancer. This data will inform genetic counseling strategies in regards to cancer risk and management. Data on additional genes updated through 2019 will be presented.