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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2018

Open Access 01-12-2018 | Research

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Authors: Mev Dominguez-Valentin, D. Gareth R. Evans, 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: Hereditary Cancer in Clinical Practice | Issue 1/2018

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Abstract

Background

In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families’ path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families’ pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2).

Methods

Women with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay.

Results

We identified 48 women who were tested negative for their family’s path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X).

Conclusion

All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.
Appendix
Available only for authorised users
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Metadata
Title
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds
Authors
Mev Dominguez-Valentin
D. Gareth R. Evans
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
01-12-2018
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2018
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/s13053-018-0086-0

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