The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis. The 23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis is indicated for reporting of the Y179C and the G396D variants in the MUTYH gene. The report describes if a person is at increased risk of developing colorectal cancer. The two variants included in this report are most common and best studied in people of Northern European descent and may not represent the majority of the MUTYH variants found in people of other ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.

Device Description

The 23andMe Personal Genome Service (PGS) is an over-the-counter (direct-to-consumer), DNA testing service that provides information and tools for consumers to learn about and explore their DNA. The 23andMe Personal Genome Service (PGS) is a currently marketed, non-invasive genetic information service that combines qualitative genotyping data covering genetic ancestry, traits, and certain heritable health conditions from a single multiplex assay with descriptive information derived from peer reviewed, published genetic research studies. It is a home use, over-the-counter (direct-to-consumer) DNA testing service intended to provide information and tools for consumers to learn about and explore their DNA. Customer saliva is self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. Once the sample is collected, it is shipped to one of our Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for testing. DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina. The multiplex assay simultaneously tests for more than 500,000 variants, including those for the previously authorized indications, as well as for the indications proposed herein. The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe. The data is then analyzed using the 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype. Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which variant(s) has/have been detected in their sample and provide information on the risk of disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and any appropriate actions that may be taken based on their results. The novel components in this traditional 510(k) submission are only (a) the variants to be reported, and (b) the qualitative reporting of risk for MAP.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the 23andMe Personal Genome Service (PGS) Genetic Health Risk Report for MUTYH-Associated Polyposis (MAP), based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance:

Study/Test	Acceptance Criteria	Reported Device Performance
Method Comparison (Accuracy)	Minimum of 99% PPA and NPA for each SNP	>99% PPA and NPA for all genotypes
Precision/Reproducibility	At least 99% correct calls at each laboratory site	100% correct genotype calls for all samples; 100% reproducibility and 100% repeatability
DNA Input	95% correct calls at a sample DNA concentration of 5 ng/μL	100% correct genotype calls for all samples and reagent lots tested at 5, 15, and 50 ng/μL
Interfering Substance (Specificity)	No new interfering substances identified (based on prior studies)	More than 35,000 sample replicates tested across four studies (endogenous, exogenous, microbial, smoking), with no discordant or No Call results across 99 SNPs, for an accuracy of 100% when following instructions for use.
Labeling Comprehension	90% or greater overall comprehension	Average comprehension rate for key concepts ranged from 90.7% to 96.1%, meeting the >90% criteria.

2. Sample Size Used for the Test Set and Data Provenance:

Accuracy (Method Comparison): Saliva samples were selected from the 23andMe customer biobank based on pre-determined BeadChip genotype and minimum volume required. The exact number of samples for the MUTYH variants specifically isn't explicitly stated, but the study compared against Sanger sequencing.
Precision/Reproducibility: Confirmed genotype DNA samples (commercially available or from 23andMe biobank) for G3696 variants and Y179C common homozygous and heterozygous variants. The Y179C rare homozygous variant was excluded. The exact number of samples for this specific study is not provided, but it involved "multiple days, operator teams, instruments, and reagent lots at two independent laboratory sites."
DNA Input: DNA samples obtained from commercial sources or 23andMe biobank based on listed genotypes. The exact number of samples for this study is not provided. The study involved diluting each sample to 3 different DNA concentrations and genotyping in a blinded fashion using 3 lots of reagents.
Interfering Substance: "More than 35,000 sample replicates were tested" across various prior studies (DEN140044).
Clinical Performance (Allele Frequencies): Frequencies are based on approximately:
- 872,000 individuals with European ancestry
- 47,500 individuals with African-American ancestry
- 38,500 individuals with Ashkenazi Jewish ancestry
- 35,000 individuals with East Asian ancestry
- 123,500 individuals with Hispanic/Latino ancestry
- 10,000 individuals with South Asian ancestry
Data Provenance: The document generally indicates the use of the 23andMe customer biobank for many of the analytical studies. For allele frequencies, it uses both the 23andMe Database and published literature (e.g., ExAc database, Poulsen and Bisgaard 2008). These would primarily be retrospective data sets from existing samples or databases.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:

The document does not explicitly state the number of experts or their qualifications for establishing ground truth for the test set specifically.

Accuracy (Method Comparison): Ground truth was established by Sanger bi-directional DNA sequencing, which is a laboratory gold standard method, not by human expert consensus or interpretation.
Precision/Reproducibility: Ground truth was established by bi-directional Sanger sequencing for each sample.
DNA Input: Ground truth was established by bi-directional Sanger sequencing for each sample.
Labeling Comprehension: Human input was used to assess comprehension rates among typical users, but these are not "experts" establishing a clinical ground truth.

4. Adjudication Method for the Test Set:

Not applicable, as the ground truth for analytical studies was primarily established by Sanger sequencing, a direct molecular method, rather than expert interpretation requiring adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The device (23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis) is a standalone genetic test for direct-to-consumer use. The studies performed focused on the analytical performance (accuracy, precision, DNA input, interfering substances) and labeling comprehension of the report itself, not on how human readers (e.g., clinicians) would improve their diagnostic accuracy with or without AI assistance. The report is intended to inform conversations with healthcare providers, not to be directly used for diagnosis or treatment decisions by those providers without confirmatory testing.

6. Standalone (Algorithm Only Without Human-in-the-Loop) Performance:

Yes, a standalone performance study was done. The vast majority of the analytical performance studies (Method Comparison, Precision/Reproducibility, DNA Input, Interfering Substances) evaluate the performance of the "23andMe BeadChip assay" and the "PGS multiplex assay" as an automated genotyping process without human intervention in the result generation. The "Coregen software" analyzes the data to determine genotypes, which are then used to generate personalized reports. This represents the algorithm's standalone performance in genotyping.

7. Type of Ground Truth Used:

Analytical Studies (Accuracy, Precision, DNA Input): Sanger bi-directional DNA sequencing was consistently used as the "truth" for genotype confirmation against which the BeadChip assay results were compared. This is considered a gold standard molecular method.
Clinical Performance: Allele frequencies were derived from the 23andMe customer database and published scientific literature/databases (e.g., ExAc database, Poulsen and Bisgaard 2008). This is not a "ground truth" for individual cases, but rather statistical data based on large populations and research findings.
Labeling Comprehension: Assessed by measuring user understanding of genetic health risk concepts, not by a clinical or pathological ground truth.

8. Sample Size for the Training Set:

The document does not provide information on the sample size used for the training set of the 23andMe PGS system or its Coregen software. The studies described are primarily analytical validation studies of the genotyping platform and the specific variants being reported. The "BeadChip" is a pre-designed array, and while software (Coregen) interprets the data, details about its specific "training" with a dataset are not available in this regulatory submission summary. The system itself (the PGS platform) was previously authorized, and this submission focuses on adding new variants.

9. How the Ground Truth for the Training Set Was Established:

As the document does not detail a specific "training set" for the genotyping algorithm or system, there is no information on how its ground truth was established. The underlying technology (Illumina Infinium BeadChip, Illumina iScan, GenomeStudio software, and 23andMe's Coregen software) is a sophisticated genotyping workflow that would have been developed and validated by the manufacturers. For the specific variants (Y179C and G396D) being reported for MUTYH-Associated Polyposis, their clinical relevance and association with disease are based on established scientific literature and understanding of genetics, rather than a training dataset for the algorithm. The analytical studies confirm the assay's ability to accurately detect these variants, with Sanger sequencing acting as the ground truth for that detection capability.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image contains the logos of the U.S. Food and Drug Administration (FDA) and the Department of Health & Human Services. The FDA logo is in blue and features the letters "FDA" followed by the words "U.S. Food & Drug Administration." The Department of Health & Human Services logo is a symbol of an eagle.

January 18, 2019

23andMe, Inc. Sarah Rys Senior Manager, Regulatory Affairs 899 W. Evelyn Ave., CA Mountain View, California 94041

Re: K182784

Trade/Device Name: MUTYH-Associated Polyposis (MAP) Regulation Number: 21 CFR 866.6090 Regulation Name: Cancer Predisposition Risk Assessment System Regulatory Class: Class II Product Code: QAZ Dated: September 28, 2018 Received: October 1, 2018

Dear Sarah Rys:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

{1}------------------------------------------------

for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Reena Philip -S

Reena Philip, Ph.D. Director Division of Molecular Genetics and Pathology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

{2}------------------------------------------------

Indications for Use

510(k) Number (if known) K182784

Device Name

23andMe Personal Genome Service (PGS) Genetic Health Risk Report for MUTYH-Associated Polyposis (MAP)

Indications for Use (Describe)

The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Risk Report for MUTYH-Associated Polyposis. The 23andMe PGS Genetic Health Risk Report for MUTYH-Associated Polyposis is indicated for reporting of the Y 179C and the G396D variants in the MUTYH gene. The report describes if a person is at increased risk of developing colorectal cancer. The two variants included in this report are most common and best studied in people of Northern European descent and may not represent the mUTYH variants found in people of other ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.

Type of Use (Select one or both, as applicable):

	Prescription Use (Part 21 CFR 801 Subpart D)
	Over-The-Counter Use (21 CFR 801 Subpart C)

_ | Prescription Use (Part 21 CFR 801 Subpart D)

|X Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

{3}------------------------------------------------

510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of Safe Medical Devices Act of 1990 and 21 CFR 807.92

The assigned 510(k) number is: K182784

Submitter / Company

Lisa Charter Director Regulatory Affairs and Supplier Quality 650-933-9455 LCharter@23andMe.com Establishment Registration Number: 3007699459 Owner Operator Number: 10029404

Company Contact

Sarah Rys Senior Manager, Regulatory Affairs 732-513-9276 SRys@23andMe.com

Date Prepared

28 September 2018

5.1 Regulatory Information

Table 5.1 Proposed new device

Type ofSubmission:	Traditional 510k
Common/UsualName:	MUTYH-Associated Polyposis (MAP)
	23andMe Personal Genome Service (PGS) Genetic Health Risk Report forMUTYH-Associated Polyposis (MAP)
RegulationName:	Cancer Predisposition Risk Assessment System
RegulationDescription:	A Cancer Predisposition Risk Assessment System is a qualitative in vitromolecular diagnostic system used for determining predisposition forcancer where the result of the test may lead to prophylactic screening,confirmatory procedures, or treatments that may incur morbidity ormortality to the patient. The test could help to inform conversations with a

{4}------------------------------------------------

	healthcare professional. This assessment system is for over-the-counteruse. This device does not determine the person's overall risk ofdeveloping any types of cancer. This test is not a substitute for visits to ahealthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.This device does not determine the person's overall risk of developing anytypes of cancer. This test is not a substitute for visits to a healthcareprovider for recommended screenings or appropriate follow-up and shouldnot be used to determine any treatments.
RegulationNumber:	21 CFR 866.6090
Product Code:	QAZ
Class	Class II
PredicateDevice:	23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (SelectedVariants) authorized on March 6, 2018 under DEN170046

5.2 Intended Use

5.3 Indications for Use

5.4. Substantially Equivalent Predicate Device

{5}------------------------------------------------

The core components of the PGS are unchanged from the de novo authorization for the predicate device, the PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) (DEN170046), and also the additional de novo Authorizations of the PGS for Carrier Screening Tests for Bloom Syndrome (DEN140044) and PGS Genetic Health Risk Reports (DEN160026), including the saliva collection kit, the reagents and beadchip, the instrumentation, the software, the test processes and procedures. The novel components in this traditional 510(k) submission are only (a) the specific variants to be reported, and (b) the qualitative reporting of risk for MAP, as opposed to the BRCA related cancer risks included in DEN170046.

As described in Section 13, the 23andMe Personal Genome Service (PGS) is a currently marketed device with reports for autosomal recessive carrier status, pursuant to DEN140044 (and related exemption), genetic health risk reports authorized as part of DEN160026 (and related exemption) and DEN170046, and features that are not considered part of the medical device (e.g. genetic ancestry and cosmetic traits such as eye or hair color).

The MAP report, scientific details, and FAQs were designed and developed in the same format as the predicate device, PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants), and conform to the submission agreements and special controls of the authorization (DEN170046). The MAP report is intended for over-the-counter, direct-to-consumer use without prescription or physician order. When a customer purchases the PGS with Health reports, the customer must first opt-in to receive carrier status and genetic health risk reports, including the Genetic Health Risk Report for MAP. Customers with positive results are advised to share their results with their healthcare provider. As instructed in predicate device authorization DEN170046. the same healthcare provider limitations are included in the package insert:

. This test is not intended to diagnose a disease, determine medical treatment or other medical intervention, or tell the user anything about their current state of health.
. This test is intended to provide users with their genetic information, which may inform health-related lifestyle decisions and conversations with their doctor or other healthcare professional.
. Any diagnostic or treatment decisions must be based on confirmatory prescription testing and/or other information that you determine to be appropriate for your patient, such as additional clinical testing and other risk factors that may affect individual risk and health care.

Thus, the 23andMe PGS Genetic Health Risk Report for MAP is substantially equivalent to the predicate, 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) authorized under DEN170046.

5.5 Device Description

The 23andMe Personal Genome Service (PGS) is an over-the-counter (direct-to-consumer), DNA testing service that provides information and tools for consumers to learn about and explore their DNA.

{6}------------------------------------------------

The 23andMe Personal Genome Service (PGS) is a currently marketed, non-invasive genetic information service that combines qualitative genotyping data covering genetic ancestry, traits, and certain heritable health conditions from a single multiplex assay with descriptive information derived from peer reviewed, published genetic research studies. It is a home use, over-thecounter (direct-to-consumer) DNA testing service intended to provide information and tools for consumers to learn about and explore their DNA.

Customer saliva is self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. (previously cleared for carrier screening indications under K141410, and the same collection kit used to generate performance data for DEN140044, DEN160026 and DEN170046), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of our Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for testing.

DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina. The multiplex assay simultaneously tests for more than 500,000 variants, including those for the previously authorized indications, as well as for the indications proposed herein.

The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe. The data is then analyzed using the 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype.

Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which variant(s) has/have been detected in their sample and provide information on the risk of disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and any appropriate actions that may be taken based on their results.

The novel components in this traditional 510(k) submission are only (a) the variants to be reported, and (b) the qualitative reporting of risk for MAP.

Engineering drawings, schematics, etc. of the MAP report are not applicable to this device.

5.6 Technological Characteristics

Test Type: Qualitative genetic test for single nucleotide polymorphism detection. Sample Type: Genomic DNA obtained from a human saliva sample. Target of detection: Single-nucleotide polymorphism. DNA extraction: Automated and manual methods. Gene: MUTYH

{7}------------------------------------------------

Variants: Y179C and G396D variants in the MUTYH gene SNPs: rs34612342 and rs36053993

Genotyping principle: The DNA is fragmented and captured on a bead array by hybridization to immobilized SNP-specific primers, followed by extension with hapten-labeled nucleotides. The primers hybridize adjacent to the SNPs and are extended with a single nucleotide corresponding to the SNP allele. The incorporated hapten-modified nucleotides are detected by adding fluorescently labeled antibodies in several steps to amplify the signals. Data analysis is performed using scatter plots.

Instrument: Illumina iScan and GenomeStudio system.

Assay results: The genotype content is separated, and then integrated into predefined report templates specific for each condition associated with each genotype.

	PredicateBRCA1/BRCA2 (SelectedVariants)DEN170046	ProposedMUTYH-AssociatedPolyposis (MAP)	SimilaritiesandDifferences
IntendedUse	The 23andMe PersonalGenome Service (PGS) usesqualitative genotyping todetect select clinicallyrelevant variants in genomicDNA isolated from humansaliva collected fromindividuals ≥18 years with theOragene Dx modelOGD500.001 for the purposeof reporting and interpretinggenetic health risks, includingthe 23andMe PGS GeneticHealth Risk Report forBRCA1/BRCA2 (SelectedVariants).	The 23andMe PersonalGenome Service (PGS) usesqualitative genotyping todetect select clinicallyrelevant variants in genomicDNA isolated from humansaliva collected fromindividuals ≥18 years for thepurpose of reporting andinterpreting genetic healthrisks, including the 23andMePGS Genetic Health RiskReport for MUTYH-Associated Polyposis(MAP).	Same PGSproduct withthe additionof 2 newvariants inthe MUTYHgene.
Indicationsfor Use	The 23andMe PGS GeneticHealth Risk Report forBRCA1/BRCA2 (SelectedVariants) is indicated forreporting of the 185delAGand 5382insC variants in theBRCA1 gene and the6174delT variant in theBRCA2 gene. The report	The 23andMe PersonalGenome Service (PGS)uses qualitative genotypingto detect select clinicallyrelevant variants in genomicDNA isolated from humansaliva collected fromindividuals ≥18 years withthe Oragene Dx model	Same PGSproduct withthe additionof 2 newvariants inthe MUTYHgene.
	describes if a woman is atincreased risk of developingbreast and ovarian cancer,and if a man is at increasedrisk of developing breastcancer or may be atincreased risk of developingprostate cancer. The threevariants included in thisreport are most common inpeople of Ashkenazi Jewishdescent and do not representthemajority oftheBRCA1/BRCA2 variants inthe general population. Thereport does not describe aperson's overall risk ofdeveloping any type ofcancer, and the absence of avariant tested does not ruleout the presence of othervariants that may be cancer-related. This test is not asubstitute for visits to ahealthcare provider forrecommended screenings orappropriate follow-up andshould not be used todetermine any treatments.	OGD500.001 for thepurpose of reporting andinterpreting genetic healthrisks, including the 23andMePGS Genetic Health RiskReport for MUTYH-Associated Polyposis. The23andMe PGS GeneticHealth Risk Report forMUTYH-AssociatedPolyposis is indicated forreporting of the Y179C andthe G396D variants in theMUTYH gene. The reportdescribes if a person is atincreased risk of developingcolorectal cancer. The twovariants included in thisreport are most commonand best studied in people ofNorthern European descentand may not represent themajority of the MUTYHvariants found in people ofother ethnicities. The testreport does not describe aperson's overall risk ofdeveloping any type ofcancer, and the absence ofa variant tested does notrule out the presence ofother variants that may becancer-related. This test isnot a substitute for visits to ahealthcare provider forrecommended screeningsor appropriate follow-up andshould not be used todetermine any treatments.
CollectionKit	Oragene-Dx® salivacollection device (OGD-500.001)	Oragene-Dx® salivacollection device (OGD-500.001)	Same

Table 5.2 Substantial Equivalence

{8}------------------------------------------------

{9}------------------------------------------------

	K141410	K141410
Reagents	Illumina Infinium HTS AssayReagents	Illumina Infinium HTS AssayReagents	Same
BeadChip	Illumina Infinium BeadChipgenotyping chip customizedfor the PGS. The chip isdesigned to detect specificsinglenucleotidepolymorphisms (SNPs) aswell as other geneticvariants; all markers refer tospecific positions intheNationalCenterforBiotechnology Information(NCBI) reference humangenome.	Illumina Infinium BeadChipgenotyping chip customizedfor the PGS. The chip isdesigned to detect specificsinglenucleotidepolymorphisms (SNPs) aswell as other genetic variants;all markers refer to specificpositions in the NationalCenter for BiotechnologyInformation (NCBI) referencehuman genome.	Same
Beadpool	Customized for 23andMe	Customized for 23andMe	Same
Instruments	Tecan EvoIllumina iScan	Tecan EvoIllumina iScan	Same
Software	Genome StudioCoregen	Genome StudioCoregen	Same
SampleMatrix	Saliva	Saliva	Same
MethodComparison	100% PPA and NPA for allgenotypes	>99% PPA and NPA for allgenotypes	Same
Precision	100% reproducibility and100% repeatability	100% reproducibility and100% repeatability	Same
MinimumDNA Input	5ng/uL	5ng/uL	Same

5.7 Performance Testing Summary

5.7.1 Method Comparison (Accuracy)

{10}------------------------------------------------

23andMe performed a Method Comparison study to assess the accuracy of the 23andMe BeadChip assay. The goal of the study was to show equivalent genotype assignment between the 23andMe BeadChip assay and Sanger bi-directional DNA sequencing. Saliva samples were selected from the 23andMe customer biobank, based on their pre-determined BeadChip genotype and minimum volume required for testing. All BeadChip genotyping was performed at an independent laboratory site. All chosen samples were then sequenced using Sanger bi-directional sequencing. Genotyping results were compared between BeadChip and sequencing to calculate positive percent agreement (PPA) and negative percent (NPA), with the sequencing results considered to be "truth." The passing criteria were a minimum of 99% PPA and NPA for each SNP. This method comparison study yielded >99% PPA and NPA for all genotypes. Therefore, the study passed the acceptance criteria of at least 99% PPA and NPA.

5.7.2 Precision/Reproducibility

23andMe performed a precision study to determine the reproducibility of the 23andMe BeadChip assay. This study included all G3696 variants, and Y179C common homozygous and heterozygous variants. The goal of the study was to evaluate the following precision parameters of the assay: intra-assay, inter-instrument, inter-operator, inter-day, and inter-lab differences. DNA samples were either commercially available samples that were available in the 23andMe biobank, and were further selected based on their confirmed genotypes. To confirm, each sample was sequenced by bi-directional Sanger sequencing. The same samples were genotyped by the BeadChip assay in a blinded fashion, with 3 lots of reagents, by multiple operator teams per day, using 3 different serial numbers of each of 2 instruments (Tecan and iScan), over 3 days, at each of 2 laboratory sites. BeadChip genotypes were compared with sequenced genotypes to determine the rates of correct BeadChip genotype calls.

This precision study yielded 100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at two independent laboratory sites. Therefore, the study passed the acceptance criteria of at least 99% correct calls at each of the two laboratory sites. There was no variation between any study conditions or any replicates for a given sample. Therefore, the study demonstrated 100% reproducibility and 100% repeatability for a given sample. Therefore, the study had 100% reproducibility and 100% repeatability.

5.7.3 DNA Input

23andMe performed a DNA input study for the 23andMe PGS multiplex assay. This study included all G3696 variants, and Y179C common homozygous and heterozygous variants. Due to the rarity of this sample type, the study excluded the Y179C rare homozygous variant.

The design of the study was consistent with our previous agreement recorded in Q160823-A001 meeting minutes dated August 9, 2016. The goal of the study was to confirm that the previously determined minimum concentration claim of 5ng/uL of DNA is necessary for successful assignment of the correct genotype using the 23andMe PGS assay. The DNA requirement for the PGS is defined as the lowest DNA concentration at which at least 95% of samples yielded the correct call. DNA samples were obtained from commercial sources or obtained from the 23andMe biobank based on their listed genotypes. Each sample was diluted to 3 different DNA

{11}------------------------------------------------

concentrations and genotyped in a blinded fashion using 3 lots of reagents. To confirm the genotype call, each sample was also sequenced using bi-directional Sanger sequencing. Genotype calls from the PGS assay were compared with sequenced genotypes to determine the rates of correct genotype calls at each DNA concentration.

This study yielded 100% correct genotype calls for all samples and all reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/μL. Therefore, the study passed the acceptance criteria of 95% correct calls at a sample DNA concentration of 5 ng/μL. This study demonstrates that the PGS tests are valid for samples with a DNA concentration range of 5 ng/yL. The performance requirement specified by contracted laboratory SOPs, is conservatively set at a minimum DNA requirement of 15 ng/μL.

5.7.4 Interfering Substance (Specificity)

The PGS requires the use of an FDA-cleared collection device (K141410). The device used for the test is the exact same device used for all carrier screening reports (DEN140044) and all genetic health risk reports (DEN160026 & DEN170046). A test for potentially interfering mutations was performed in support of DEN140044, and no new interfering substances have been identified. The cleared device includes instructions for use instructing the user to not eat, drink, smoke or chew gum for 30 minutes prior to collecting their saliva, thus minimizing the availability of interferents in the sample. 23andMe performed a series of studies to assess the effects of endogenous substances, exogenous substances, microbial substances, and smoking on the 23andMe PGS assay in support of submission DEN140044. Over these four studies, more than 35,000 sample replicates were tested, with no discordant or No Call results across 99 SNPs, for an accuracy of 100% when following the instructions for use (i.e., nothing by mouth for at least 30 minutes prior to collecting saliva).

5.7.5 Potentially Interfering Mutations

23andMe has identified three (3) potentially interfering mutations near Y179C, and four (4) potentially interfering mutations near G396D that are within the binding region of the probes for the variants of interest. The Company was unable to identify commercially available samples for these potentially interfering mutations, therefore has added a statement in the limitations section of the package insert stating that the impact of interfering mutations has not been evaluated.

5.7.6 Matrix Comparison

Human saliva is the only suitable sample matrix Comparison studies are not applicable.

5.7.7 Shelf Life

The PGS requires the use of the same FDA-cleared collection device that was reviewed and cleared in submission K141410. Shelf life data, summarized below, was previously reviewed and authorized in K141410, DEN140044, DEN160026, and DEN170046.

Pre-collection shelf-life conditions were evaluated by storing unused Oragene-Dx® devices at room temperature, 6°C ± 4°C or -20°C ± 5°C for up to 24 months. Devices were exposed to

{12}------------------------------------------------

multiple freeze/thaw cvcles of -20°C ± 5°C/50°C ± 5°C. In a separate study, devices were sent by standard mail to donors for collection and the donors mailed their samples directly to the processing laboratories. At all study time points a subset of devices were evaluated for physical and chemical properties to ensure the product specifications remained within acceptable tolerances. Another subset of devices was used to collect saliva from which DNA was extracted and analyzed for yield and A260/A280 ratio. The data supports shelf-life claims of room temperature storage for up to 24 months. Additionally, the devices may be transported by standard mail at temperatures ranging from -20℃ ± 5℃ to 50℃ ± 5℃.

Post-collection sample stability of the Oragene-Dx® device was evaluated by having 30 donors each self- collect saliva samples using Oragene-Dx® OGD-500. Samples were stored at room temperature, 6°C ± 4°C or -20°C ± 5°C for 12 months or at 50°C ± 5°C for 3 months. At all study time-points, DNA was extracted and analyzed for yield and A260/A280 ratio. Samples stored at room temperature were analyzed for microbial content using a real-time PCR-based assay. The data supports post-collection storage at -20°C to room temperature for up to 12 months and at 50°C ± 5°C for 3 months.

5.7.8 Clinical Performance

The clinical sensitivity and specificity are estimated based on published studies of variant frequencies in various populations and the results of analytical studies reported in this submission, as well as allele frequencies in the 23andMe customer base for the genetic variants and associations included in this submission.

The following table summarizes the clinical performance data for the PGS Genetic Health Risk Report for MAP.

Table 5.3 Clinical Performance

Allele Frequencies (%): in the 23andMe Database, and from published literatures

Ancestry group	Y179C		G396D
	23andMe	Published	23andMe	Published
European	0.21%	0.25%c0.20%d	0.58%	0.40%c0.40%d
African American	0.06%	0.05%e	0.21%	0.11%e
Ashkenazi Jewish	0.00%	Unknown	0.00%	Unknown
East Asian	0.00%	0.00%0.00%f	0.01%	0.01%0.00%f
Hispanic/Latino	0.14%	0.10%	0.51%	0.33%

{13}------------------------------------------------

South Asian	0.03%	0.00%	0.03%	0.02%
-------------	-------	-------	-------	-------

a Based on approximately 872,000 individuals with European ancestry, 47,500 individuals with African-American ancestry, 38,500 individuals with Ashkenazi Jewish ancestry, 35,000 individuals with East Asian ancestry, 123,500 individuals with Hispanic/Latino ancestry, and 10,000 individuals with South Asian ancestry. Because of the privacy considerations surrounding the use of customer data (namely, the risk of exposing the identity of individuals in the database), the frequencies provided are rounded to a hundredth of a percent and truncated at a minimum frequency if the number of individuals with a variant is fewer than five.

b Unless a reference is specified, the data was extracted from ExAc database:

http://exac.broadinstitute.org/ accessed 18Jun2018.

6 European (Non-Finnish)

d Poulsen and Bisgaard 2008, data from USA population

e African

' Poulsen and Bisgaard 2008, data from Japanese population

5.7.9 Labeling Comprehension

The comprehension of key report concepts were determined to be the same as those identified and previously tested in the predicate device label comprehension study (DEN170046). The average comprehension rate per comprehension concept ranged from 90.7% to 96.1%, therefore the comprehension study met the predefined acceptance criteria of 90% or greater overall comprehension.

The representative Genetic Health Risk reports and supporting educational materials were effective in communicating relevant concepts to users unfamiliar with genetic testing sufficient for the safe use of the PGS Genetic Health Risk Report for MAP.

5.8. Discussion

The PGS Genetic Health Risk Report for MAP has a similar intended use as the predicate, is not technologically different than the predicate, and therefore presents no new issues of safety or effectiveness when compared to the previously authorized predicate device (DEN170046). Specifically, this submission for the PGS Genetic Health Risk Report for MAP provides analytical and clinical data demonstrating that the PGS Test generates an accurate result, and that the user can adequately interpret the result for both of the variants.

5.9. Conclusion

The PGS Genetic Health Risk Report for MAP is substantially equivalent to the predicate device DEN170046 (23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants), authorized March 6, 2018). As presented, the PGS Genetic Health Risk Report for MAP is a safe and effective consumer product that can safely and effectively assist and encourage women and men with positive results to engage in potentially life saving conversations with their healthcare provider.

{14}------------------------------------------------

Regulation Number and Section

§ 866.6090 Cancer predisposition risk assessment system.

(a)
Identification. A cancer predisposition risk assessment system is a qualitative in vitro molecular diagnostic system used for determining predisposition for cancer where the result of the test may lead to prophylactic screening, confirmatory procedures, or treatments that may incur morbidity or mortality to the patient. The test could help to inform conversations with a healthcare professional. This assessment system is for over-the-counter use. This device does not determine the person's overall risk of developing any types of cancer. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10 of this chapter and any pre-purchase page and test report generated, unless otherwise specified, must include:
(i) An intended use that specifies in the indications for use the genetic variants detected by the test. The specific variants must be appropriately validated as described in paragraphs (b)(4)(xii) and (b)(4)(xiii) of this section.
(ii) A section addressed to users with the following information:
(A) A warning statement accurately disclosing the genetic coverage of the test in lay terms, including information on variants not queried by the test, and the proportion of pathogenic variants in the genes that the assay detects in a specific population as identified in paragraph (b)(1)(i) of this section. The warning statement must indicate that the test [does not/may not, as appropriate] detect all genetic variants related to the genetic disease, and that the absence of a variant tested does not rule out the presence of other genetic variants that may impact cancer risk. The warning statement must also include the relevant population for which the variants reported by the test are most relevant.
(B) A limiting statement explaining that some people may feel anxious about getting genetic test health results. This is normal. If the potential user feels very anxious, such user should speak to his or her doctor or other healthcare professional prior to collection of a sample for testing. This test is not a substitute for visits to a doctor or other healthcare professional. Users should consult with their doctor or other healthcare professional if they have any questions or concerns about the results of their test or their current state of health.
(C) A limiting statement that a user's ethnicity may affect whether the test is relevant for them and may also affect how their genetic health results are interpreted.
(D) A warning statement that the test is not a substitute for visits to a healthcare professional for recommended screenings, and should not be used to determine any treatments or medical interventions.
(E) A warning statement that the test does not diagnose cancer or any other health conditions and should not be used to make medical decisions. The warning statement must indicate that the results should be confirmed in a clinical setting before taking any medical action.
(F) A limiting statement explaining that other companies offering a genetic risk test may be detecting different genetic variants for the same disease, so the user may get different results using a test from a different company.
(G) If applicable, a limiting statement that states the test does not test for variants in other genes linked to hereditary cancer.
(H) A limiting statement explaining that this test does not account for non-genetic factors and that other factors such as environmental and lifestyle risk factors may affect the risk of developing a given disease.
(I) Information to a potential purchaser or actual test report recipient about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counseling.
(J) A limiting statement explaining that this test is not intended to tell you anything about your current state of health, or be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take.
(K) A limiting statement explaining that the laboratory may not be able to process a sample, and a description of the next steps to be taken by the manufacturer and/or the customer, as applicable.
(iii) A section in the labeling required under § 809.10 of this chapter and any test report generated that is for healthcare professionals who may receive the test results from their patients with the following information:
(A) A limiting statement explaining that this test is not intended to diagnose a disease, determine medical treatment or other medical intervention, or tell the user anything about their current state of health.
(B) A limiting statement explaining that this test is intended to provide users with their genetic information to inform health-related lifestyle decisions and conversations with their doctor or other healthcare professional.
(C) A limiting statement explaining that any diagnostic or treatment decisions should be based on confirmatory prescription testing and/or other information that is determined to be appropriate for the patient (
e.g., additional clinical testing and other risk factors that may affect individual risk and health care).(2) The genetic test must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.
(3) The device's labeling must include a hyperlink to the manufacturer's public website where the manufacturer must make the information identified in paragraph (b)(3) of this section publicly available. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a hyperlink to the web page containing this information and must allow unrestricted viewing access. If the device can be purchased from the website or testing using the device can be ordered from the website, the same information must be found on the web page for ordering the device or provided in a publicly accessible hyperlink on the web page for ordering the device. Any changes to the device that could significantly affect safety or effectiveness would require new data or information in support of such changes, which must also be posted on the manufacturer's website. The information must include:
(i) An index of the material being provided to meet the requirements in paragraph (b)(3) of this section and its location.
(ii) Technical information about the device, as specified in paragraph (b)(4) of this section.
(iii) A section that highlights summary information that allows the user to understand how the test works and how to interpret the results of the test. This section must, at a minimum, be written in plain language understandable to a lay user and include:
(A) Consistent explanations of the risk of disease associated with all variants included in the test, variants not included in the test, and specific considerations by ethnicity. If there are different categories of risk, the manufacturer must provide literature references and/or data that support the different risk categories. If there will be multiple test reports and multiple variants, the risk categories must be defined similarly among them. For example, “increased risk” must be defined similarly between different test reports and different variant combinations.
(B) Clear context for the user to understand the context in which the cited clinical performance data support the risk reported. This includes any risks that are influenced by ethnicity, age, gender, environment, and lifestyle choices.
(C) Materials that explain the main concepts and terminology used in the test that include:
(
1 ) Definitions: scientific terms that are used in the test reports.(
2 ) Pre-purchase page: this page must contain information that informs the user about what information the test will provide. This includes variant information, the condition(s) or disease(s) associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test (e.g., test does not detect all variants related to the disease), relevance of race/ethnicity, and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in page must be provided. This opt-in page must be provided for each disease type that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:(
i ) An option to accept or decline to receive this specific test result;(
ii ) Specification of the risk involved if the user is found to have the specific genetic test result;(
iii ) Summary of professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended;(
iv ) A recommendation to speak with a healthcare professional, genetic counselor, or equivalent professional before getting the results of the test;(
v ) The implications of receiving a no variants detected result; and(
vi ) The statement that the test does not diagnose cancer or any other health conditions and should not be used to make medical decisions. Results should be confirmed in a clinical setting before taking any medical action. Users should consult with a healthcare professional before taking any medical action.(
3 ) Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding peer-reviewed publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity to the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risk factors that contribute to disease, appropriate follow-up procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.(4) The device labeling must include a technical information section containing the following information:
(i) Gene(s) and variant(s) the test detects using standardized nomenclature, Human Genome Organization (HUGO) nomenclature and coordinates, as well as Single Nucleotide Polymorphism Database (dbSNP) reference SNP numbers (rs#).
(ii) A statement indicating that more than 1,000 variants in the BRCA1 and BRCA2 genes are known to increase cancer risk, as applicable.
(iii) Scientifically established disease-risk association of each variant detected and reported by the test. This risk association information must include:
(A) Genotype-phenotype information for the reported variants.
(B) When available, a table of expected frequency in the general population and different ethnicities, and risks of developing the disease in relevant ethnic populations and the general population.
(C) Information such as peer-reviewed published literature and/or professional guidelines used to determine what types and levels of evidence will distinguish whether the selected variants are reported as “are associated with increased risk” versus “may be associated with increased risk” of developing other cancers. All selected variants must be appropriately validated as required under paragraph (b)(1)(i) of this section. For selected variants reported as “are associated with increased risk,” the clinical evidence must be demonstrated with sufficient information (
e.g., professional guidelines and consistent associations in peer-reviewed published literature). For the selected variants reported as “may be associated with increased risk,” the clinical evidence must be reported in professional guidelines, but peer-reviewed published literature may not be consistent.(D) A statement about the current professional guidelines for testing these specific gene(s) and variant(s) for the specified disease(s).
(
1 ) If professional guidelines are available, provide the recommendations in the professional guideline(s) for the gene, variant, and disease for when genetic testing should or should not be performed, and cautionary information that should be communicated when a particular gene and variant is detected.(
2 ) If professional guidelines are not available, provide a statement that the professional guidelines are not available for these specific gene(s) and variant(s).(iv) The specimen type (
e.g., saliva, whole blood).(v) Assay steps and technology used.
(vi) Specification of required ancillary reagents, instrumentation, and equipment.
(vii) Specification of the specimen collection, processing, storage, and preparation methods.
(viii) Specification of risk mitigation elements and description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(ix) Information pertaining to the probability of test failure (
e.g., percentage of tests that failed quality control) based on data from clinical samples, a description of scenarios in which a test can fail (e.g., low sample volume, low DNA concentration), how users will be notified of a test failure, and the nature of follow-up actions on a failed test to be taken by the user and the manufacturer.(x) When available, information specifying the probability of a false negative and false positive analytical result and any additional considerations by ethnicity.
(xi) Specification of the criteria for test result interpretation and reporting, including any distinctions between risk categories (
i.e., increased risk and greatly increased risk; are associated and may be associated).(xii) Information that demonstrates the performance characteristics of the test including:
(A) Accuracy of study results for each claimed specimen type.
(
1 ) Accuracy of the test must be evaluated with fresh clinical specimens collected and processed in a manner consistent with the test's instructions for use. If this is impractical, fresh clinical samples may be substituted or supplemented with archived clinical samples. Archived samples must have been collected previously in accordance with the instructions for use, stored appropriately, and randomly selected. In some limited circumstances, use of contrived samples or human cell line samples may also be appropriate and used as an acceptable alternative. The contrived or human cell line samples must mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the test's accuracy.(
2 ) Accuracy must be evaluated by comparison to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and the test must be pre-defined and appropriate to the test's intended use. Detailed study protocols must be provided.(
3 ) Information provided must include the number and type of specimens, broken down by clinically relevant variants for each indicated report that were compared to bidirectional sequencing or other methods identified as appropriate by FDA. The accuracy as positive percent agreement (PPA) and negative percent agreement (NPA) must be measured, and accuracy point estimates must be >99 percent (both per reported variant and overall). Uncertainty of the point estimate must be within an acceptable range, as identified by FDA, and must be presented using the 95 percent confidence interval.(
4 ) Sufficient specimens must be tested per genotype and must include all genotypes that will be included in the tests and reports. The number of samples tested in the accuracy study for each variant reported must be based on the variant frequency.(
5 ) Any no calls (i.e., absence of a result) or invalid calls (e.g., failed quality control) in the study must be included in accuracy study results and reported separately. The percent of final 'no calls' or 'invalid calls' must be clinically acceptable. Variants that have a point estimate for PPA or NPA of