Genetic variants of prospectively demonstrated phenocopies in kindreds.

BACKGROUND

In kindreds carrying 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' but also be capable of causing cancer in the absence of the variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families' pathogenic variant ( or ).

METHODS

Women with BC or gynecological cancer who had tested negative for or 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 ( = 13) or ( = 35) variants. Pathogenic variants in the and genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from and 9% (3/35) from families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing ( c.721G > A, c.764A > G and c.815C > T). However, by using a minigene, assay we here show that c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the c.764A > G. The c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the 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.