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A variety of unusual tumors are associated with both germline and somatic DICER1 pathogenic variants (PVs), including, in the female genital tract, embryonal rhabdomyosarcoma at various sites and ovarian Sertoli-Leydig cell tumor. There have been occasional reported cases of ovarian germ cell tumors [mainly yolk sac tumor (YST)] harboring DICER1 PVs but, as far as we are aware, none of these has been proven to have a germline provenance. We report an unusual enteric variant of ovarian YST in a 28-yr-old woman associated with a germline PV c.901CT (p.Gln301Ter) in exon 7 of DICER1, accompanied by a somatic (YST-only) hotspot mutation: c.5437GA, p.E1813K. To our knowledge, this is the first report of an ovarian germ cell tumor associated with a germline DICER1 PV. We review other reported cases of ovarian germ cell tumor with DICER1 PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma.

Introduction Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. Methods Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. Results Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. Discussion Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.