SARS-CoV-2 has undergone a broad process of recombination since identification of the prototype strain in 2019, introducing a huge number of mutations in its genome and generating a vast array of variants of interest (VoI) and concern (VoC). Many of such variants developed several mutations in Spike protein and RBD, with the new Omicron (B.1.1.529) strain displaying over 30 changes, 15 of which concentrated in the RBD. Besides their impact on virus biology, as well as on the risk of detection failure with some molecular techniques (i.e. S gene dropout), recent evidence suggests that these mutations may also jeopardize the reliability of currently available commercial immunoassays for detecting anti-SARS-CoV-2 antibodies.