title: CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site.
abstract: Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5' splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Zarina
authors.identifier: http://orcid.org/0000-0003-4517-0751
authors.initials: Z
authors.lastname: Yelskaya
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bacares
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Salo-Mullen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Somar
authors.affiliation: Department of Hematology Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lehrich
authors.affiliation: Department of Surgical Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, United States of America.
authors.forename: Grace-Ann
authors.initials: GA
authors.lastname: Fasaye
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Coit
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D015703:Antigens, CD; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D022821:RNA Splice Sites; D012326:RNA Splicing; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D022821:RNA Splice Sites