Next Article in Journal
Identification of an Embryonic Cell-Specific Region within the Pineapple SERK1 Promoter
Previous Article in Journal
Sow Thistle Chloroplast Genomes: Insights into the Plastome Evolution and Relationship of Two Weedy Species, Sonchus asper and Sonchus oleraceus (Asteraceae)
Open AccessArticle

The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability

1
Department of Pathology, Landspitali - The National University Hospital of Iceland, 101 Reykjavik, Iceland
2
BMC (Biomedical Center), Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
3
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
4
Department of Oncology, Landspitali, The National University Hospital of Iceland, 101 Reykjavik, Iceland
*
Author to whom correspondence should be addressed.
Genes 2019, 10(11), 882; https://doi.org/10.3390/genes10110882
Received: 16 August 2019 / Revised: 4 October 2019 / Accepted: 29 October 2019 / Published: 1 November 2019
(This article belongs to the Special Issue Functional Role of BRCA 1 and 2 in Tissue Maintenance and Neoplasia)
Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.
Keywords: BRCA1; VUS; LOH; breast cancer; ovarian cancer; tumorigenesis; Knudson's two-hit model; cancer risk; homozygous lethality BRCA1; VUS; LOH; breast cancer; ovarian cancer; tumorigenesis; Knudson's two-hit model; cancer risk; homozygous lethality
MDPI and ACS Style

Arason, A.; Agnarsson, B.A.; Johannesdottir, G.; Johannsson, O.T.; Hilmarsdottir, B.; Reynisdottir, I.; Barkardottir, R.B. The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability. Genes 2019, 10, 882.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop