Consider the following scenario:
You have a Microsoft Exchange Server 2013 hybrid environment.
You install Cumulative Update 6 on the on-premises Exchange Server 2013 server.
You enable centralized mail transport in the hybrid deployment.
Note Centralized mail transport routes outgoing email messages from the Exchange Online mailboxes through your on-premises Exchange servers. For more information, see Transport routing in Exchange 2013 hybrid deployments.
A user whose mailbox is located in Office 365 sends an email message to an external recipient.
In this scenario, the email message is not delivered successfully, and the user receives a non-delivery report (NDR) that contains the following error message:
550 5.7.1 Unable to relay
This issue occurs because centralized mail transport does not work in Cumulative Update 6.
To resolve this issue, install Cumulative Update 7 for Exchange Server 2013.
Microsoft has confirmed that this is a problem in the Microsoft products that are listed in the "Applies to" section.