A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families

Abstract

Communicated by Jacques S. BeckmannThe 185delAG and 5382insC founder mutations account for the majority of mutations identified in BRCA1 in Ashkenazi Jewish breast and breast-ovarian cancer families. Few non-founder BRCA1 mutations have been identified to date in these families. We initially screened a panel of 245 Ashkenazi Jewish breast-ovarian cancer families with an affected proband and at least one other case of breast or ovarian cancer for founder mutations in BRCA1 and BRCA2. Founder mutations were identified in 85 families (185delAG in 44 families, 5382insC in 16 families, and the BRCA2 6174delT in 25 families). The 160 negative families were then screened for the entire BRCA1 gene by a combination of DGGE and PTT. We identified one novel frameshift mutation in BRCA1 in exon 14 (4572del22) that truncated the protein at codon 1485. The family contained three cases of early-onset ovarian cancer (41 years, 43 years, and 52 years) and one case of breast cancer (at age 54 years subsequent to an ovarian cancer). In addition, three missense variants of unknown significance (exon 11 C3832T (P1238L), exon 15 G4654T (S1512I), and exon 15 G4755A (D1546N)) were found in single families.

The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

“…Within the Ashkenazi Jewish group, 45 of 47 (96%) point mutations were founder mutations. Our data are consistent with previous studies, demonstrating that the founder mutations account for more than 90% of mutations in Ashkenazi Jewish women (50, 51). In total, reported in the literature and including our study, 99 Ashkenazi Jewish probands from high risk families have been negatively screened for genomic rearrangements (48).…”

The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

“…Within the Ashkenazi Jewish group, 45 of 47 (96%) point mutations were founder mutations. Our data are consistent with previous studies, demonstrating that the founder mutations account for more than 90% of mutations in Ashkenazi Jewish women (50, 51). In total, reported in the literature and including our study, 99 Ashkenazi Jewish probands from high risk families have been negatively screened for genomic rearrangements (48).…”

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

“…The lower prevalence in the current study may be the result of sample size and ascertainment differences. Similar to our study, Phelan et al (Phelan et al 2002) identified 1 (0.6 %) non-founder mutation in a group of 160 AJ families presenting for genetic evaluation and screened for BRCA1 mutations. The prevalence of a mutation may have been slightly higher had BRCA2 sequencing also been included as in the current study.…”

BRCA1 (185delAG) Mutation among Egyptian Breast Cancer Female Patients

“…Other studies reported frequencies of 1.9% (26) and 2% (27) (31) found that the frequency of the mutation was not different between the unilateral and bilateral BC patients and explained the development of bilateral BC to familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 mutation. Other studies reported a mutation frequency of 20% (32) to 100% (33) (Result ) Our finding is higher than that reported by Friedman et al, (36) (7.4%) and…”

The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

“…Within the Ashkenazi Jewish group, 45 of 47 (96%) point mutations were founder mutations. Our data are consistent with previous studies, demonstrating that the founder mutations account for more than 90% of mutations in Ashkenazi Jewish women (50, 51). In total, reported in the literature and including our study, 99 Ashkenazi Jewish probands from high risk families have been negatively screened for genomic rearrangements (48).…”

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

“…The lower prevalence in the current study may be the result of sample size and ascertainment differences. Similar to our study, Phelan et al (Phelan et al 2002) identified 1 (0.6 %) non-founder mutation in a group of 160 AJ families presenting for genetic evaluation and screened for BRCA1 mutations. The prevalence of a mutation may have been slightly higher had BRCA2 sequencing also been included as in the current study.…”

BRCA1 (185delAG) Mutation among Egyptian Breast Cancer Female Patients

“…Other studies reported frequencies of 1.9% (26) and 2% (27) (31) found that the frequency of the mutation was not different between the unilateral and bilateral BC patients and explained the development of bilateral BC to familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 mutation. Other studies reported a mutation frequency of 20% (32) to 100% (33) (Result ) Our finding is higher than that reported by Friedman et al, (36) (7.4%) and…”

The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

“…Within the Ashkenazi Jewish group, 45 of 47 (96%) point mutations were founder mutations. Our data are consistent with previous studies, demonstrating that the founder mutations account for more than 90% of mutations in Ashkenazi Jewish women (50, 51). In total, reported in the literature and including our study, 99 Ashkenazi Jewish probands from high risk families have been negatively screened for genomic rearrangements (48).…”

To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

“…The lower prevalence in the current study may be the result of sample size and ascertainment differences. Similar to our study, Phelan et al (Phelan et al 2002) identified 1 (0.6 %) non-founder mutation in a group of 160 AJ families presenting for genetic evaluation and screened for BRCA1 mutations. The prevalence of a mutation may have been slightly higher had BRCA2 sequencing also been included as in the current study.…”

BRCA1 (185delAG) Mutation among Egyptian Breast Cancer Female Patients

“…Other studies reported frequencies of 1.9% (26) and 2% (27) (31) found that the frequency of the mutation was not different between the unilateral and bilateral BC patients and explained the development of bilateral BC to familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 mutation. Other studies reported a mutation frequency of 20% (32) to 100% (33) (Result ) Our finding is higher than that reported by Friedman et al, (36) (7.4%) and…”