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01-01-2018 | Original Article

Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families

Authors: Mev Dominguez-Valentin, Sigve Nakken, Hélène Tubeuf, Daniel Vodak, Per Olaf Ekstrøm, Anke M. Nissen, Monika Morak, Elke Holinski-Feder, Alexandra Martins, Pål Møller, Eivind Hovig

Published in: Familial Cancer | Issue 1/2018

Abstract

To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.

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Title: Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families
Authors: Mev Dominguez-Valentin
Sigve Nakken
Hélène Tubeuf
Daniel Vodak
Per Olaf Ekstrøm
Anke M. Nissen
Monika Morak
Elke Holinski-Feder
Alexandra Martins
Pål Møller
Eivind Hovig
Publication date: 01-01-2018
Publisher: Springer Netherlands
Published in: Familial Cancer / Issue 1/2018
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-017-0011-0

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