In a major upset, House Majority Leader Eric Cantor (R-VA), the second-ranking Republican in the U.S. House, was defeated on Tuesday night by a college professor who had won the backing of Tea Party groups, dealing a major setback to the GOP Establishment and opening the way for an internal Republican fight over who might succeed House Speaker John Boehner.

"It's disappointing, sure," Cantor told his supporters after his defeat. "But I believe in this country, I believe there's opportunity around the next corner for all of us."

"Wow," was all one Republican U.S. Senator could say when informed of Cantor's loss.

The clues to Cantor's defeat were certainly there, but his backers had assured fellow Republicans that they would defeat economics professor David Brat, a political novice.

But Brat won easily in Virginia's 7th Congressional District, where Tea Party forces back in May had defeated Cantor's hand-picked candidate for local Republican Party chairman, and convention attendees had booed Cantor loudly when he jabbed at Brat.

Along with the bad reception at that GOP gathering, the decision by Cantor to go negative in TV ads back in March can now be seen as an admission of weakness - as the Cantor people seemed to realize they needed to attack Brat to have a chance to win the GOP primary.

Here was one of those ads:

But while Cantor far outspent Brat, the negative ads did not work - and the final tally wasn't even close, as Brat had over 55% of the vote with almost all precincts reporting.

It was evidently the first time a sitting House Majority Leader had lost in a primary since the position was created in 1899.

The last time a sitting Speaker of the House was defeated by voters was in 1994, when Democrat Tom Foley of Washington State was ousted.

Cantor loss shakes up U.S. House GOP

For the last few years, many saw Cantor as the logical person to replace Speaker John Boehner, and with some conservatives trying to build a grass roots effort to push Boehner out, many assumed Cantor could be Speaker as early as next year.

But now that is not going to happen, as Cantor won't be in the House come January of 2015; he is the second sitting lawmaker to lose a bid for re-election this year.

44 members of the House now won't be back in 2015 for the new Congress.

Many will also see the Cantor loss as a rejection of immigration reform, as there had been a lot of speculation that GOP leaders would try to move a bill after this year's primaries were over.

"We can't stop illegal immigration unless we stop Eric Cantor," was one of Brat's calls during this campaign, as he urged voters to "take your country back and stop amnesty for good."

Some will say it shows that immigration reform is a non-starter with Republicans - but, while Cantor tried to nuance his position on immigration reform and lost, Sen. Lindsey Graham (R-SC) was fully involved in reform efforts - and yet he easily won his primary in South Carolina on Tuesday.

Even bigger than immigration, maybe the biggest impact will be within the House GOP, where a group of more conservative Republicans already wants to boot Speaker Boehner and try something new.

Cantor's defeat could add even more fuel to that internal Republican call for change at the top.

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