A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay

• DOI: 10.1101/mcs.a003012
• Publication Date: 2018-05-24T21:10:27Z
• Authors: Kate Krempely; Rachid Karam
• Keywords: CDH1; Nonsense-Mediated Decay; Nonsense; Proband; Nonsense mutation

Most truncating cadherin 1 ( CDH1 ) pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer (DGC) and lobular breast (LBC). However, transcripts containing carboxy-terminal premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay pathway, risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing because a personal history invasive LBC diagnosed at age 54, which identified germline nonsense alteration, c.2506G>T (p.Glu836*), in last exon gene. Subsequent parental for alteration was negative additional short tandem repeat analysis confirmed familial relationships de novo occurrence proband. Based on occurrence, clinical history, rarity general population databases, this classified as likely variant. This is most reported date. Additionally, contributed classification six other upstream variants or pathogenic. Identifying distal provides evidence classify either benign, fundamental step offering presymptomatic screening prophylactic procedures appropriate patients.