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Expanded genetic testing guidelines for hereditary cancers, increased utilization of large multigene panels, and improved methods for reclassifying variants have led to a greater need to understand how variant reclassification and patient re‐contact are managed. This study aimed to describe the process of variant reclassification and subsequent patient re‐contact at a comprehensive cancer genetic counseling service in a large metropolitan medical center with several statewide satellite locations. A retrospective chart review was performed to identify reclassified variants between 1/1/1997 and 12/1/2020. In total, 8.4% (211/2503) of variants were reclassified over the 24‐year period, which includes multiple cases involving the same unique variant. Several variants underwent more than one reclassification, resulting in 232 total reclassifications among 194 individuals. Nearly all reclassifications were prompted by the laboratory (99.1%; 230/232) rather than the genetics clinic staff. Overall, 10.3% (24/232) of all reclassifications were upgrades, but only 9.1% (21/232) led to a change in management recommendations. The median time for variant reclassification was 1.7 years (interquartile range [IQR] = 0.8–3.2 years). There was no statistically significant difference in the time to reclassification for White patients (median = 1.6 years; IQR = 0.8–2.8 years) compared to non‐White patients (median = 2.0 years; IQR = 0.9–3.7 years; Mann–Whitney U = 4,764.0, p = 0.066). Patient re‐contact was attempted for 97.4% (226/232) of variants and was always performed by a genetic counselor, most often through a mailed letter (85.8%, 194/226). Specifically for reclassifications that led to a change in management recommendations, re‐contact was always attempted, most often through combined telephone and mailed letter (95.2%; 20/21). Overall, the median time from reclassification to attempted patient re‐contact was 13 days (range: 0–589 days). The characterization of this clinic's reclassification and re‐contact procedures can serve as an example for other genetics clinics trying to incorporate re‐contact into their workflow.

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>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.

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.

Background There are racial and ethnic differences in the prevalence and types of pathogenic mutations and variants of uncertain significance (VUS) in BRCA1 and BRCA2. Since the landmark May 13, 2013 Supreme Court Ruling invalidating the patent for BRCA1 and BRCA2 genetic testing, numerous gene panels have been utilized to identify individuals at high risk for hereditary disease due to mutations in other cancer predisposing genes. 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 data base from May 13, 2013 through December, 31, 2018. The cohort consisted of 3,544 unrelated individuals evaluated for high-risk of hereditary disease and 1,868 who had panel testing at 6 sites across Michigan including Detroit. We estimated the prevalence of pathogenic mutations and VUS from multigene panels by race and ethnicity. Odds Ratios (OR) and 95% confidence intervals (CI) were calculated to compare the rate of pathogenic mutations and VUS in race and ethnic groups with non-Hispanic whites (NHW) indicated as the reference group. Results There were 1,868 (52.7%) individuals who had panel testing which included 67.4% NHW, 24.1% African American (AA), 2.2% Arab, 1.9% Ashkenazi Jewish (AJ), 1.0% Hispanic (H), and 3.4% other. There were 174 individuals with pathogenic mutations and 312 with VUS. Compared to NHW, AA individuals were less likely to have pathogenic mutations on multi-panel testing (OR, 95% CI, 0.20, 0.10-0.37) and more likely to have VUS (OR, 95% CI, 1.41, 1.07-1.85). There were no differences in pathogenic mutations or VUS for other race or ethnic groups. Within a common 18 gene panel (excluding BRCA1 and BRCA2), the five most common genes with a pathogenic mutation were ATM (23), CHEK2 (21), PALB2 (13) and MSH6 (11). The three most common genes and number of pathogenic mutations identified by race and ethnicity were NHW (ATM -21, CHEK2-21&MSH6 -8), AA (MSH6-1, RAD51C-1&TP53-1), and Arab (PALB2-2, RAD50-1 and BARD1-1). For AJ individuals there were 2 pathogenic mutations identified in the MSH6 gene. There were no pathogenic mutations seen in Hispanics. Conclusions Understanding the prevalence of mutations in multi-gene panels in specific racial and ethnic groups can lead to better identification of individuals at risk for hereditary cancer who can benefit from enhanced surveillance and risk reducing management. Citation Format: Michael Steven Simon, Nadine Abdallah, Hadeel Assad, Malini Surapaneni, Rachel Reagle, Nancie Petrucelli, Kristen Purrington. Racial and ethnic variation in multi-gene panel 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 P6-08-22.