RNA sequencing uncovers clinically actionable germline intronicMSH2variants in previously unresolved Lynch syndrome families

Abstract

Despite advances in genetic testing for Lynch syndrome, nearly one quarter of mismatch repair-deficient (MMRd) colorectal and endometrial cancers remain unexplained. When added to germline DNA testing, RNA sequencing can increase diagnostic yield, improve variant classification and reduce variants of uncertain significance. Here, we describe two cases where RNA sequencing uncovered likely pathogenicMSH2variants in families with MMRd tumours that were initially unexplained following comprehensive genetic testing for Lynch syndrome.