Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel

Abstract

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.

FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns

“…The Oncogenetics Unit recruited women who were counselled and genotyped for being at high risk for developing breast/ovarian cancer as determined by standard criteria (Laitman et al, 2012) and were subsequently found to harbour either a BRCA1 or BRCA2 mutation (see below). The Oncogenetics Unit recruited women who were counselled and genotyped for being at high risk for developing breast/ovarian cancer as determined by standard criteria (Laitman et al, 2012) and were subsequently found to harbour either a BRCA1 or BRCA2 mutation (see below).…”

“…(ii) Analysis of the predominant Jewish mutations in the BRCA1/BRCA2 genes Mutational analyses for two of the three founder mutations (185delAG in BRCA1 and 6174delT in BRCA2) were carried out by restriction enzyme digest of PCR products, and analysis of the digested PCR products on agarose gels as previously described by us (Laitman et al, 2012). For each of these mutations, a known mutation carrier was used as a positive control in each experiment and each mutation was confirmed by sequencing.…”

Recurrent Germline BRCA2 Gene Mutation in Lithuanian Family

“…BRCA2 c.3847_3848delGT (4075delGT, rs80359405) pathogenic mutation causes frameshift and generates mutant p.V1283fs * 2 protein. This type of BRCA2 mutation is uncommon among the Ashkenazi population [11] but is quite widespread in northern and western Europe, being one of five most frequently observed mutations. In 26 Lithuanian families, Rebbeck et al [6] described 11 unique mutations, and the five most frequently observed BRCA2 mutations included c.658_659del (13), c.3847_3848del (4), c.6580dup (1), c.6410del (1) and c.7879A>T (1).…”

Recapitulating the clinical scenario of BRCA‐associated pancreatic cancer in pre‐clinical models

“…At initial diagnosis germline DNA from each patient was subjected to both BRCA1 and BRCA2 sequence analysis by BRACAnalysis CDx™ test for clinical evaluation which was performed by Myriad Genetic Laboratories (Salt Lake City, UT); or mutational analyses which were carried out by restriction enzyme digest of PCR products, to introduce a restriction site that distinguishes between the wild type and the mutant allele and analysis of the digested PCR products on agarose gels as previously described . The mutation resulted in a different fragment pattern from the wild type allele.…”