Functional Analysis and Clinical Data Reclassify the DICER1 c.4206+ 1G >C Variant, Leading to Exon 22 Skipping, as Likely Pathogenic

ABSTRACT Pathogenic germline variants in DICER1 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli‐Leydig cell tumour and a broader spectrum of pathologies. Here, we report a 35‐year‐old female with diagnoses of pineoblastoma, embryonal rhabdomyosarcoma, leiomyosarcoma, two meningiomas, and a germline DICER1 c.4206+ 1G >C, p.(?) variant. The variant was classified as a variant of unknown significance ( VUS ) based on the current ACMG / AMP gene‐specific DICER1 guidelines. Additional functional analysis showed that the variant clearly abrogates the function of DICER1 and therefore PS3_Supporting evidence is included in the classification. Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG / AMP gene‐specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence ( PS3 ) code.