Assessment of 1863 GRIN2A Variants Contradicts a Role in Tumorigenesis

GRIN2A has previously been identified as frequently mutated in tumor samples, leading to a hypothesized involvement of GRIN2A in tumorigenesis. Pathogenic GRIN2A germline variants, on the other hand lead, to neurodevelopmental disorders, with no evidence for tumor burden. Thus, we aimed for an independent assessment of somatic and germline variation in GRIN2A, hypothesizing that a distinct distribution of somatic variation indicates a tumorigenic effect. All publicly available GRIN2A variants were obtained from ClinVar, gnomAD and Cosmic to account for germline variation in affected individuals and the general population, as well as somatic variation. Functional consequences, mutational hotspots and gene expression were assessed for each dataset to draw conclusions on the potential pathomechanisms of tumorigenesis. Pathogenic germline variants in GRIN2A expose a clear genotype-phenotype association and are predominantly present in functionally relevant domains, while somatic GRIN2A variants exhibit a uniform distribution and no high abundance in functionally relevant domains. The expression of GRIN2A is lower in tumor samples compared to in non-diseased tissues. Given the non-uniform distribution and domain clustering, our results suggest that specific domains of GRIN2A are highly intolerant towards germline variation, while a lack of somatic mutational clustering and functional relevance refutes the previously hypothesized major role of GRIN2A in tumorigenesis.