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

Mutations in result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is c.4096+3A>G, which affects production of the full-length 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 ( = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and -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 -mutation. Our findings add to the current knowledge of and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.