BRCA1 and BRCA2 mutation spectrum – an update on mutation distribution in a large cancer genetics clinic in Norway

Abstract

BackgroundFounder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.MethodsA total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.ResultsThere were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.ConclusionsThe spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway’s largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

“…Other variants that also lead to skipping of exon 23 have been published as pathogenic, e.g. c.5407-2A>G [11,26], c.5407-10G>A [27], c.5467+1G>A [28] and c.5434C>G (p.Pro1812Ala) [11,29]. Although a wide range of alternative transcripts have been described for the BRCA1 locus [12], there were no signs of aberrant splicing of exon 23 among the 30 normal controls in our study.…”

“…Nevertheless, the BRCA1 variant c.5434C>G is considered a high-risk pathogenic/likely pathogenic variant by several independent groups [11,18,29]. However, most partial splice variants remain VUS [19], leaving patients and doctors in a challenging position.…”

“…The PCR products were analysed by agarose gel electrophoresis and Sanger sequencing. The reference sequence NG_005905.2 (NM_007294.3) and traditional numbering of exons [1][2][3][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] was used.…”

Screening of BRCA1/2 genes mutations and copy number variations in patients with high risk for hereditary breast and ovarian cancer syndrome (HBOC)

“…It was detected in a patient suffering from ovarian cancer. To the best of our knowledge, this is the first Moroccan study to report this variant however, it was reported in different populations worldwide [61,62].…”

Female family members lack understanding of indeterminate negative BRCA1/2 test results shared by probands

“…Participants were excluded if they had a personal history of any type of cancer besides nonmelanoma skin cancer, had ever received genetic counseling or BRCA1/2 testing themselves, had a prophylactic mastectomy or oophorectomy, lived outside the United States, and/or were incarcerated. Women of Ashkenazi Jewish descent were not included because of their elevated risk due to the prevalence of founder mutations in BRCA1/2 (Heramb et al, ).…”