The primary objective is to confirm the specificity of a multi-target stool DNA test (mt-sDNA), Cologuard, in an average risk population, ages 45-49.

Subjects aged 45-49 at average risk for development of CRC will be enrolled. Subjects will complete the mt-sDNA screening test (Cologuard) followed by completion of a screening colonoscopy. The results of the mt-sDNA screening test (Cologuard) will not be provided to investigators for clinical management of study subjects. Personnel performing the colonoscopy and producing the resulting report and personnel performing histopathological review of tissue (if applicable) will remain blinded to the results of the mt-sDNA screening test (Cologuard) result.

Inclusion Criteria:

Subjects must meet the following criteria to be eligible for the study:

1. Subject is at average risk for development of CRC.
2. Subject is able and willing to undergo a screening colonoscopy.
3. Subject is ≥ 45 and ≤ 49 years of age at the time of enrollment.
4. Subject is willing and able to sign informed consent.
5. Subject is able and willing to provide stool sample(s) according to written instructions provided.

Exclusion Criteria:

1. Subject has a history of CRC or adenoma.
2. Subject has ≥2 first-degree relatives who have been diagnosed with CRC
3. Subject has one first-degree relative with CRC diagnosed before the age of 60.
4. Subject has any of the following: Overt rectal bleeding, e.g., hematochezia or melena within the previous 30 days (blood on toilet paper, after wiping, does not constitute rectal bleeding). Positive fecal occult blood test or FIT within the previous six (6) months. Subject has had a previous colonoscopy. Subject has undergone any double-contrast barium enema, virtual (CT-based) colonoscopy, or flexible sigmoidoscopy within the previous five (5) years.
5. Subject has a diagnosis or personal history of any of the following conditions, including: Familial adenomatous polyposis (also referred to as "FAP", including attenuated FAP and Gardner's syndrome). Hereditary non-polyposis CRC syndrome (also referred to as "HNPCC" or "Lynch Syndrome").Other hereditary cancer syndromes including but are not limited to Peutz-Jeghers Syndrome, MYH-Associated Polyposis (MAP), Turcot's (or Crail's) Syndrome, Cowden's Syndrome, Juvenile Polyposis, Neurofibromatosis and Familial Hyperplastic Polyposis.
6. Subject has a family history of: Familial adenomatous polyposis (also referred to as "FAP"), Hereditary non-polyposis CRC syndrome (also referred to as "HNPCC" or "Lynch Syndrome").
7. Subjects with Cronkhite-Canada Syndrome.
8. Subject has a diagnosis of inflammatory bowel disease (IBD) including chronic ulcerative colitis (CUC) and Crohn's disease.
9. Subject has a history of aerodigestive tract cancer.
10. Subject has had a prior colorectal resection for any reason other than sigmoid diverticular disease.
11. Subject has any condition that in the opinion of the investigator should preclude participation in the study.

Subjects 45-49 years of age who are at average risk for development of CRC. 942 subjects are targeted to enroll.

Individual participant data that underlie the results reported in publications of the study will be shared after de-identification. This may include text, tables, figures, and appendices. The study protocol, statistical analysis plan, informed consent form, and clinical study report will also be shared. Data will be shared with researchers who provide a methodologically sound proposal to achieve the aims outlined in the approved proposal.

Data will be available from 2 years and ending 4 years after publication.

Proposals for access to data should be directed to clinicaltrials@exactsciences.com. To gain access, data requestors will need to provide a methodologically sound proposal and sign a data access agreement. Researchers are required to obtain necessary IRB/EC approvals or waivers as applicable to conduct research.

Principal Investigator agreed that they shall not, without the Sponsor's prior written consent, independently publish, publicly disclose, present or discuss any results of or information pertaining to the activities conducted under their agreement for a period of one (1) year following completion of the Study.