ClinVar

Breast-Ovarian Cancer Susceptibility

Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer.

Struewing et al. (1995) pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation.

Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (600185.0009). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2.

Bar-Sade et al. (1997) examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to Bar-Sade et al. (1997) that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ.

Bar-Sade et al. (1998) extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently.

Bandera et al. (1998) demonstrated the 185delAG mutation in 2 women with a personal or family history of breast cancer and papillary serous carcinoma of the peritoneum (PSCP). PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma and it may develop years after oophorectomy. Schorge et al. (1998) demonstrated that the tumors were multifocal in these cases, indicating that patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas.

Ah Mew et al. (2002) reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population.

Buisson et al. (2006) found that BRCA1 transcripts bearing the 185delAG mutation are not degraded by nonsense-mediated mRNA decay. Using Western blot analysis, they examined HeLa cells transfected with minigenes for this transcript and another with a premature termination codon at position 36 and found that translation from these transcripts was reinitiated at codon 128.

Pancreatic Cancer Susceptibility

Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; 614320) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 185delAG mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs.