Background: MAPK1 encodes ERK2, a kinase component of the mitogen activated signaling (MAPK) pathway. ERK2 E322K is a known activating mutation that leads to increased phosphorylation and ERK signaling. In vitro studies found this mutation to be associated with resistance to dabrafenib, trametinib, but potential sensitivity to ERK inhibitors. Despite its potential as a drug target, little is known about the clinicopathologic characteristics of this hotspot mutation across solid tumors. Methods: Patients with solid tumors underwent tumor next-generation sequencing at Memorial Sloan Kettering Cancer Center between Jan 2015 and Sep 2020 using the MSK-IMPACT assay. Using the cBioPortal database and clinical charts, we analyzed tumors harboring MAPK1/ERK2 E322K mutations, assessed their clinicopathologic characteristics, co-mutational status and overall survival (OS). OS was measured from time of tumor sequencing to date of death or last follow-up. Results: A total of 37 tumor samples from 35 patients were identified in 59,822 tumors sequenced (0.06%) to harbor an ERK2 E322K mutation. The distribution across tumor types was as follows: head and neck squamous cell carcinoma (29%), bladder cancer (20%), lymphomas (9%), colorectal cancers (9%), gastric cancers (9%), cholangiocarcinoma (6%), cervical cancers (6%), lung cancers (6%), germ cell tumor (3%), Merkel cell carcinoma (3%), and breast cancers (3%). The OS in patients with metastatic disease and ERK2 E322K was 22.29 months (95%CI: 7.56-NA) months. Other mutations in RAS pathway frequently co-occurred with ERK2 E322K mutation (17/37, 46%). Concurrent mutations are also involved in pathways of cell cycle (71%), PI3K (71%), TP53 (66%), NOTCH (57%), RTK (51%), HIPPO (29%), TGF-beta (29%), WNT (26%), NRF2 (20%), MYC (14%). The median TMB score of samples from solid malignancies was 12.3 (range:0-101, quartiles: 6.9-33.0) mutation/Mb. Two patients (2/35, 6%) had microsatellite-instability high (MSI-H) tumors. The most frequent concurrent activating mutations include ARID1A (29%), FBXW7 (26%), PI3KCA (22%), PI3KR1/2/3 (20%), CDKN2A (11%), PTEN (8%), BRCA1/2(8%), FGFR3 (8%), BRAF (6%), Only one of these 35 patients received treatment targeting BRAF/MEK/ERK pathway and achieved partial response. One patient with NSCLC harboring a concurrent EGFR L858R mutation did not respond to erlotinib. One patient with PI3KCA mutated head and neck cancer did not respond to PI3K inhibitor. Two patients had TMB score of 100.9 and 12.9 mutation/Mb had partial response to pembrolizumab. Conclusions: ERK2 E322K mutation is a rare oncogenic mutation across diverse solid tumor types, associated with a high co-occurrence of other activating mutations and a high TMB. The lack of response to other targeted therapies suggests ERK2 E322K is a potential driver mutation. These findings may inform treatment and further development of ERK inhibitors.