Dr Lee has long harboured doubts about the current Brexit strategy, but has chosen to act just hours before the whips were carefully counting the numbers.
Tory Remainer rebels have long suggested that a number of ministers have privately encouraged their efforts and indicated possible resignations.
Dr Lee, a practicing doctor whose Berkshire constituency neighbours the prime minister’s and is well known to her, indicated he will vote against the government in the crucial “meaningful vote” division this afternoon.
He described ministers’ plan to only allow MPs to choose between “no deal” and its deal as a “fake choice” between a bad deal and even worse, which he “cannot countenance”.
He shocked Westminster by announcing his resignation away from the cameras at a conference of the Tory think-tank Bright Blue.
“When MPs vote on the House of Lords’ amendments to the EU (Withdrawal) Bill, I will support the amendment, which will empower parliament to reject a bad deal and direct the government to re-enter discussions,” Dr Lee said.
“For me, this is about the important principle of parliamentary sovereignty.”
He also backed a referendum on the terms of the exit deal, saying: “When the government is able to set out an achievable, clearly defined path – one that has been properly considered, whose implications have been foreseen, and that is rooted in reality not dogma – it should go to the people, once again, to seek their confirmation.”
The resignation and the threat of more ministers following suit have thrown the numbers for this and subsequent votes up in the air.
The government was already facing a knife-edge calculation as to whether to accept a Dominic Grieve compromise amendment on the “meaningful vote”, tabled last night.
It had been receiving some encouragement from former rebels including Nicky Morgan, but Mr Grieve and other former ministers such as Ken Clarke and Anna Soubry were standing firm.
The question now is will other MPs who share Phillip Lee’s concerns follow suit, today or in the coming weeks?