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

Most truncating cadherin 1 (CDH1) pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). However, transcripts containing carboxy-terminal premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay pathway,...

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Autores principales: Krempely, Kate, Karam, Rachid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071572/
https://www.ncbi.nlm.nih.gov/pubmed/29798843
http://dx.doi.org/10.1101/mcs.a003012
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author Krempely, Kate
Karam, Rachid
author_facet Krempely, Kate
Karam, Rachid
author_sort Krempely, Kate
collection PubMed
description Most truncating cadherin 1 (CDH1) pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). However, transcripts containing carboxy-terminal premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing because of a personal history of invasive LBC diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c.2506G>T (p.Glu836*), in the last exon of the gene. Subsequent parental testing for the alteration was negative and additional short tandem repeat analysis confirmed the familial relationships and the de novo occurrence in the proband. Based on the de novo occurrence, clinical history, and rarity in general population databases, this alteration was classified as a likely pathogenic variant. This is the most carboxy-terminal pathogenic alteration reported to date. Additionally, this alteration contributed to the classification of six other upstream CDH1 carboxy-terminal truncating variants as pathogenic or likely pathogenic. Identifying the most distal pathogenic alteration provides evidence to classify other carboxy-terminal truncating variants as either pathogenic or benign, a fundamental step to offering presymptomatic screening and prophylactic procedures to the appropriate patients.
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spelling pubmed-60715722018-08-13 A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay Krempely, Kate Karam, Rachid Cold Spring Harb Mol Case Stud Rapid Cancer Communication Most truncating cadherin 1 (CDH1) pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). However, transcripts containing carboxy-terminal premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing because of a personal history of invasive LBC diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c.2506G>T (p.Glu836*), in the last exon of the gene. Subsequent parental testing for the alteration was negative and additional short tandem repeat analysis confirmed the familial relationships and the de novo occurrence in the proband. Based on the de novo occurrence, clinical history, and rarity in general population databases, this alteration was classified as a likely pathogenic variant. This is the most carboxy-terminal pathogenic alteration reported to date. Additionally, this alteration contributed to the classification of six other upstream CDH1 carboxy-terminal truncating variants as pathogenic or likely pathogenic. Identifying the most distal pathogenic alteration provides evidence to classify other carboxy-terminal truncating variants as either pathogenic or benign, a fundamental step to offering presymptomatic screening and prophylactic procedures to the appropriate patients. Cold Spring Harbor Laboratory Press 2018-08 /pmc/articles/PMC6071572/ /pubmed/29798843 http://dx.doi.org/10.1101/mcs.a003012 Text en © 2018 Krempely and Karam; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Rapid Cancer Communication
Krempely, Kate
Karam, Rachid
A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title_full A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title_fullStr A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title_full_unstemmed A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title_short A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay
title_sort novel de novo cdh1 germline variant aids in the classification of carboxy-terminal e-cadherin alterations predicted to escape nonsense-mediated mrna decay
topic Rapid Cancer Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071572/
https://www.ncbi.nlm.nih.gov/pubmed/29798843
http://dx.doi.org/10.1101/mcs.a003012
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