Paired tumor-germline DNA testing can provide an informative result regarding a Lynch syndrome (LS) diagnosis for up to 76% of patients. Recent studies show that, when added to germline DNA testing, RNA analysis has the potential to increase diagnostic yield, improve variant classification, and reduce variants of uncertain significance (VUS).
We describe the addition of this RNA testing to aid in the diagnostic evaluation of these 23 patients whose MMRd tumor and clinical histories suggestive of LS remained unexplained following paired tumor-germline DNA analysis.
Patients with MMRd colon or endometrial tumors, negative LS germline DNA testing, and previous tumor DNA testing showing only a single somatic mutation in MLH1, MSH2 (EPCAM), MSH6, or PMS2 were invited to participate.
Of 23 patients undergoing supplemental RNA testing, one (4.3%) was positive for a germline LS likely pathogenic variant (VLP).
RNA analysis identified the MSH2 c.2459-12A>G VLP in a female diagnosed with endometrioid carcinoma exhibiting loss of MSH2 protein on immunohistochemistry.
The proband’s family history met Amsterdam II criteria and her affected brother (rectal cancer) and sister (colon polyps) were also positive for the same intronic VLP
1/23 patients (4.3%) received a diagnosis of LS via RNA testing after identifying only a single somatic LS mutation, thus altering medical management for that patient and her family. Supplemental RNA testing can increase the diagnostic yield in a cohort of patients with previous unresolved paired tumor-germline LS DNA testing.

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