Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-toconsumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 selfreported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx). Direct-to-consumer (DTC) genetic testing is gaining in popularity in the United States. An increasing number of people are choosing to learn about how genetics may inform their ancestry, health predispositions, and common traits. In October 2018, the US Food and Drug Administration (FDA) granted 23andMe the first authorization of a DTC test for detecting genetic variants associated with the metabolism of certain medications. 1 With this authorization, 23andMe can provide consumers information about variants in eight pharmacogenes. Most of those variants are part of the cytochrome P450 (CYP) superfamily of enzymes, which are involved in 70-80% of all phase I drug metabolism and bioactivation. 2 Ethnicity-dependent polymorphisms in these genes account for up to 30% of interindividual variations in

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2 Background: Pharmacogenetic (PGt) testing holds great potential for supporting clinical decision making and optimizing medication outcomes for cancer patients. Genetic variants in the DPYD gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity, and can cause severe fluoropyrimidine-related toxicity. However, the clinical uptake of PGt testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) PGt test will improve access to PGt testing. This study assessed the frequency of two DPYD variants, c.1905+1G > A (*2A) and c.2846A > T (D949V), in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped using Illumina genotyping arrays that included the DPYD c.1905+1G > A and c.2846A > T variants. Eligible subjects were 23andMe U.S. customers who were at least 18 years of age and consented to participate in research. IRB approval was obtained from Ethical & Independent Review Services. Results: Out of approximately 6.4 million eligible participants included in this analysis, the overall allele frequencies of DPYD c.1905+1G > A and c.2846A > T were 0.42% and 0.47%, respectively. People of Ashkenazi Jewish, South Asian, and European descent had the highest frequencies (0.56%, 0.56%, and 0.47%, respectively) for the DPYD c.1905+1G > A variant, and people of European and Hispanic/Latino descent had the highest frequencies (0.55% and 0.43%, respectively) for the DPYD c.2846A > T variant. Conclusions: This is the first description of an unselected cohort of individuals with DPYD c.1905+1G > A and c.2846A > T variants identified through DTC genetic testing. Preemptive DTC PGt testing can help disseminate potentially clinically useful information to a large number of consumers.

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63 Background: MUTYH-associated polyposis (MAP) is an autosomal recessive condition that accounts for about 0.3-0.7% of all colorectal cancer (CRC) cases. The two most common variants among people of Northern European descent are MUTYH Y179C (rs34612342) and G396D (rs36053993), with a carrier frequency of 1-2%. However, understanding the frequency of these variants in other populations can better inform population health approaches for CRC screening and prevention. This study assessed the frequency of these two variants in a generally unselected group of genotyped individuals who have used direct-to-consumer (DTC) genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped on Illumina genotyping arrays, which included the Y179C and G396D variants. Eligible subjects were 23andMe customers who were at least 18 years of age and who consented to participate in research. IRB approval was obtained from Ethical and Independent Review Services. Results: Out of the 3,617,279 eligible participants included in this study, the overall allele frequencies of Y179C and G396D were 0.18% and 0.51%, respectively. People of European descent had the highest frequencies (0.22% and 0.59%), while people of Ashkenazi Jewish, East Asian, and South Asian descent had the lowest frequencies ( < 0.015% for both variants). The allele frequencies for people of Hispanic/Latino descent were 0.15% and 0.51%. Conclusions: This is the first description of an unselected cohort of individuals with MUTYH Y179C and G396D variants identified through DTC genetic testing. While these two variants were most common among people of European descent, they were also observed at relatively high frequency among people of Hispanic/Latino descent. These results may help guide CRC screening and prevention strategies in different ethnicities.