Hereditary breast and ovarian cancer. Diversity of genetic causes of HBOC in a Norwegian breast and ovarian cancer patient cohort, BRCA2 c.8331+2C>T - a Norwegian founder mutation

Abstract

Hereditary breast and ovarian cancer (HBOC) causes 5-10 % of breast cancer cases and 25 % of ovarian cancer cases. About 24 % of HBOC are caused by deleterious variants in BRCA1 and BRCA2. Currently, more than 25 different genes have been associated with HBOC, including BRCA1 and BRCA2, many of which encode proteins participating in homologous recombination repair (HRR) and mismatch repair (MMR).

In one part of this study, 16 genes associated with HBOC were scrutinised using next generation sequencing (NGS) on 48 patient samples where no deleterious variants or variants of unknown clinical significance (VUS’s) had previously been found in BRCA1 or BRCA2. Among five of the 48 patients included in this study, three different deleterious variants were identified including: ATM c.3245_3247delinsTGAT, TP53 c.818G>A and CHEK2 c.319+2T>A. In addition, eight different VUS’s in 5 different genes were identified in ATM, BRIP1, MLH1, NF1 and PMS2.

In the second part of this study, the BRCA2 c.8331+2C>T variant, which has been identified in 29 families in Norway, was found to cause skipping of exon 18. Both the high frequency of the BRCA2 c.8331+2C>T variant in Norwegian breast cancer families and the currently conducted microsatellite analysis with markers in close proximity to the BRCA2 gene, indicated that this variant is a Norwegian founder mutation.The variant was estimated to be 97-215 generations old.