Document

We have acted as special counsel to Exact Sciences Corporation, a Delaware corporation (the “Company”) in connection with the Registration Statement on Form S-8 (the “Registration Statement”) to be filed by the Company on the date hereof with the Securities and Exchange Commission (the “SEC”) under the Securities Act of 1933, as amended (the “Securities Act”), and the rules and regulations promulgated thereunder, for the registration of the following shares of the Company’s common stock, par value $0.01 per share (“Common Stock”): (i) 11,735,501 shares of Common Stock (the “2025 Plan Shares”) pursuant to the Exact Sciences Corporation 2025 Omnibus Long-Term Incentive Plan (the “2025 Plan”); and (ii) 4,000,000 shares of Common Stock (the “ESPP Shares”) pursuant to the Exact Sciences Corporation 2010 Employee Stock Purchase Plan (as amended and restated on July 31, 2024) (the “A&R ESPP”), as amended by the Amendment to Exact Sciences Corporation 2010 Employee Stock Purchase Plan (as amended and restated on July 31, 2024) (the “2025 ESPP Amendment” and the A&R ESPP, as amended by the 2025 ESPP Amendment, the “Stock Purchase Plan”, and together with the 2025 Plans, the “Plans” and each a “Plan”).

(c) the Sixth Amended and Restated Certificate of Incorporation of the Company as filed with the Secretary of State of the State of Delaware (the “Secretary of State”) on February 5, 2001, as amended by the Certificate of Designations of Series A Junior Participating Preferred Stock of the Company as filed with the Secretary of State on February 23, 2011, as amended by the Certificate of Change of Location of Registered Office and of Registered Agent of the Company as filed with the Secretary of State on September 24, 2012, as amended by the Certificate of Amendment to Sixth Amended and Restated Certificate of Incorporation of the Company as filed with the Secretary of State of July 24, 2014, as amended by the Certificate of Elimination of Series A Junior Participating Preferred Stock of the Company as filed with the Secretary of State on October 25, 2018, as amended by the Certificate of Amendment to Sixth Amended and Restated Certificate of Incorporation of the Company as filed with the Secretary of State on July 23, 2020, as amended by the Certificate of Merger of Domestic Limited Liability Company into Domestic Corporation as filed with the Secretary of State on December 28, 2021, as amended by the Certificate of Ownership and Merger Merging Sampleminded, Inc. into the Company as filed with the Secretary of State on December 23, 2022, as amended by the Waiver of Requirement for Affidavit of Extraordinary Event Condition as filed with the Secretary of State on December 23, 2022, and as amended by the Certificate of Amendment to Sixth Amended and Restated Certificate of Incorporation of the Company as filed with the Secretary of State on June 9, 2023;

(e) resolutions adopted by the board of directors of the Company (the “Board”) on (i) April 15, 2025 approving (x) the 2025 Plan, the reservation of the 2025 Plan Shares and the filing of the Registration Statement with respect to the 2025 Plan Shares and (y) the 2025 ESPP Amendment, the reservation of the ESPP Shares and the filing of the Registration Statement with respect to the ESPP Shares, and (ii) on July 31, 2024 approving the A&R ESPP;

For purposes of rendering our opinion below, we have not reviewed any document other than the Reviewed Documents and assume there exists no provision in any document relating to the matters covered by our opinion below that we have not reviewed that is inconsistent with the Reviewed Documents or our opinion below. We have conducted no independent factual investigation of our own but rather have relied on the documents listed above, the statements and information set forth therein and the additional matters recited or assumed herein, all of which we assume to be true, complete and accurate in all respects.

For purposes of this opinion letter, we have made assumptions that are customary in opinion letters of this kind, including the assumptions that: (a) each of the Reviewed Documents is accurate and complete; (b) each of the Reviewed Documents that is an original is authentic; (c) each of the Reviewed Documents that is a copy conforms to an authentic original; (d) all signatures on each of the Reviewed Documents are genuine; and (e) there are no documents other than the Reviewed Documents that could affect the opinion expressed in this opinion letter and no amendments, modifications or waivers of the Reviewed Documents. We have further assumed (i) the legal capacity of natural persons, (ii) that each party to the Reviewed Documents (A) is duly organized, validly existing and in good standing under the laws of its organization, (B) has the legal capacity, power and authority to execute, deliver and perform its obligations under the Reviewed Documents to which it is a party, (C) has taken all action necessary to duly authorize the execution and delivery of, and the performance of such party’s obligations under, the Reviewed Documents, and (D) has duly executed and delivered the Reviewed Documents, (iii) the Reviewed Documents constitute the legal, valid and binding obligation of each party thereto, enforceable against each such party in accordance with their terms, (iv) the issuance of the Shares will not increase the proportionate share of Common Stock held by an “interested stockholder” (within the meaning of Section 203(c) of the General Corporation Law of the State of Delaware (the “DGCL”)), and (v) the Company is and shall remain at all times a corporation duly incorporated, validly existing and in good standing under the laws of the State of Delaware. We have not verified any of the foregoing assumptions.

In rendering our opinion below, we also have assumed that (a) the Company will have sufficient authorized, unissued and unreserved shares of Common Stock at the time of each issuance of a Share or rights or options to acquire a Share, in each case, under the Plans; (b) either (i) upon the issuance of a Share, such Share will be evidenced by a certificate that has been duly executed and delivered or (ii) the Board has adopted a resolution providing that all shares of Common Stock shall be uncertificated in accordance with Section 158 of the DGCL prior to the issuance of such Share and, within a reasonable time after the issuance of such uncertificated Share, the registered owner of such Share will be given notice in writing or by electronic transmission in compliance with Section 151(f) of the DGCL; (c) the issuance of each Share will be duly recorded in the Company’s stock ledger upon its issuance; (d) each Plan and each Award Agreement (as defined in the 2025 Plan and hereinafter referred to as an “Award Agreement”) constitutes or will constitute, as applicable, the valid and binding agreement of the Company, enforceable against the Company in accordance with its terms; (e) the Company will receive consideration for each Share as set forth in the applicable Authorizing Resolutions (as defined below), which consideration shall be at least equal to the par value of such share of Common Stock (unless such Share is held in treasury, in which case, the consideration shall be the amount as set forth in the applicable Authorizing Resolutions), and, in the amount required by the applicable Plan and any applicable Award Agreement; (f) with respect to any Shares issuable upon the exercise of any right or option to acquire Shares under the Plans, the Company shall have received the minimum consideration (if any) for which such rights or options may be issued pursuant to the applicable Authorizing Resolutions and the applicable Plan; and (g) prior to (i) the issuance of any 2025 Plan Shares

or any right or option to acquire any 2025 Plan Shares, in each case, under the 2025 Plan, the Board or a duly authorized committee of the Board will duly authorize by resolution each Award (as defined in the 2025 Plan) granted under the 2025 Plan with respect such 2025 Plan Shares or rights or options to acquire such 2025 Plan Shares and pursuant to an Award Agreement, in each case, in accordance with the DGCL and the 2025 Plan, and (ii) the issuance of options to acquire any ESPP Shares under the Stock Purchase Plan, the Board or a duly authorized committee of the Board will authorize by resolution the number of ESPP Shares to be issued upon exercise of such options and the Offering Period, the Exercise Date, the Options and the Option Price (each as defined in the Stock Purchase Plan) with respect to options to acquire Shares, in each case, in accordance with the DGCL and the Stock Purchase Plan (such resolutions, collectively, the “Authorizing Resolutions”). We have not verified any of the foregoing assumptions.

We hereby consent to the filing of this opinion letter with the SEC as Exhibit 5.1 to the Registration Statement. In giving this consent, we do not thereby admit that we are experts with respect to any part of the Registration Statement within the meaning of the term “expert” as used in Section 11 of the Securities Act or the rules and regulations promulgated thereunder by the SEC, nor do we admit that we are within the category of persons whose consent is required under Section 7 of the Securities Act or the rules and regulations of the SEC promulgated thereunder.


			K&L GATES LLP 300 SOUTH TRYON STREET SUITE 1000 CHARLOTTE, NC 28202 T +1 704 331 7400 F +1 704 331 7598 klgates.com


			Yours truly,

			/s/ K&L Gates, LLP

			K&L Gates LLP