Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

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

doi:10.1186/s13053-018-0086-0

Abstract

BackgroundIn 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).MethodsWomen 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.ResultsWe 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).ConclusionAll 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.

Highlights

In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant
History and clinical characteristics In total, we identified 48 cases, of whom 18 breast cancer (BC) or gynecological cancer patients who did not carry their respective families’ path_BRCA1 or path_BRCA2 variants (n = 13 and n = 5, respectively) came from the Hereditary Cancer Biobank from the Norwegian Radium Hospital, while the Department of Genomic Medicine from the University of Manchester identified a total of 30 BC patients, all non-carriers of the family’s path_BRCA2 variants (Fig. 1)
Germline findings In the 48 cases, we identified five (10%) to carry pathogenic variants in ATM (c.468G > A, p.Trp156Ter and c.9139C > T, p.Arg3047Ter), BRCA2 (c.9382C > T, p.Arg3128Ter), MSH6 (c.2864delC, p.Thr955fs) and MUTYH (c.1178G > A, p.Gly393Asp)

Summary

Introduction

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 may increase the susceptibility of the families’ path_BRCA1/2, and be capable of causing cancer in the absence of the path_BRCA1/2 variants. It has been proposed that these families may have additional genetic variants, which may increase the susceptibility of the families’ path_BRCA1/2, and be capable of causing cancer in the absence of the path_BRCA1/2 demonstrated in the families [5,6,7]

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