The primary objective of this study is to assess the sensitivity for colorectal cancer (CRC) and specificity of the mt-sDNA 2.0 test.

Subjects 40 years of age and older scheduled for a screening colonoscopy will be enrolled. Subject will complete the mt-sDNA 2.0 test and the commercially available FIT, followed by completion of a screening colonoscopy. The results of the mt-sDNA screening test and FIT will not be provided to investigators for clinical management of the study subject. Personnel performing the colonoscopy and producing the resulting report and personnel performing histopathologial review of reports or tissue (if applicable) will remain blinded to the results of the mt-sDNA 2.0 screening test results.

Inclusion Criteria:

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

1. Subject is ≥ 40 years of age at the time of enrollment.
2. Subject presents for a screening colonoscopy per standard of care.
3. Subject has no symptoms or signs that require immediate, or near term, referral for diagnostic or therapeutic colonoscopy.
4. Subject is able and willing to sign informed consent

Exclusion Criteria:

1. Subject has a history of CRC or advanced precancerous lesions.

2. Subject has a diagnosis or medical / family 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, or Familial Hyperplastic Polyposis.

3. Subject has a diagnosis or personal history of inflammatory bowel disease (IBD) including chronic ulcerative colitis and/or Crohn's disease.

4. Subject has a diagnosis of Cronkhite-Canada Syndrome.

5. Subject has had a positive Cologuard within the previous 2 years, or fecal occult blood test or FIT within the previous 6 months.

6. Subject has undergone a colonoscopy within the previous 9 years with the exception of a failed colonoscopy due to poor bowel preparation. Failed colonoscopy must have been within the past year and without therapeutic intervention.

7. Subject has had overt rectal bleeding within the previous 30 days.

8. Subject has any condition that in the opinion of the Investigator should preclude participation in the study.

Subjects 40 years of age and older who are eligible for CRC screening and scheduled for a screening colonoscopy. 24,000 subjects are targeted to enroll.

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

Data may 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.