Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families

Abstract

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.

Reflex Testing for GermlineBRCA1,BRCA2,PALB2, andATMMutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

“…14 No large genomic changes in BRCA1, BRCA2, PALB2, or ATM were identified in our FC Study case series. Consistent with these findings are reports showing absence of large genomic changes in BRCA1, BRCA2, and/or PALB2 in families with breast/ovarian cancer with FC ancestry, 22,42,52,53 AJ ancestry, 54 and ethnically diverse families. 13,41,55,56 Large genomic changes in ATM are also rare.…”

Reflex Testing for GermlineBRCA1,BRCA2,PALB2, andATMMutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

“…14 No large genomic changes in BRCA1, BRCA2, PALB2, or ATM were identified in our FC Study case series. Consistent with these findings are reports showing absence of large genomic changes in BRCA1, BRCA2, and/or PALB2 in families with breast/ovarian cancer with FC ancestry, 22,42,52,53 AJ ancestry, 54 and ethnically diverse families. 13,41,55,56 Large genomic changes in ATM are also rare.…”

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

“…Large rearrangements were not identified in the BRCA1/2 genes (n=26) in our cohort of AJ individuals testing negative for founder and non-founder point mutations, which is consistent with previous reports (Palma et al 2008;Stadler et al 2010). These data are consistent with prior studies showing that founder mutations continue to account for the vast majority of all mutations in this population and suggest that routine screening for large rearrangements does not seem to be warranted in AJ individuals.…”

Analysis of BRCA1 and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

“…To date, at least 81 different large genomic rearrangements have been found in BRCA1 gene and account for 8%–27% of all BRCA1 mutations. Alternatively Alu sequences are less common in BRCA2 gene, where only few large genomic rearrangements are reported, accounting for 0%–11% of all BRCA2 mutations [19-21]. …”

Reflex Testing for GermlineBRCA1,BRCA2,PALB2, andATMMutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

“…14 No large genomic changes in BRCA1, BRCA2, PALB2, or ATM were identified in our FC Study case series. Consistent with these findings are reports showing absence of large genomic changes in BRCA1, BRCA2, and/or PALB2 in families with breast/ovarian cancer with FC ancestry, 22,42,52,53 AJ ancestry, 54 and ethnically diverse families. 13,41,55,56 Large genomic changes in ATM are also rare.…”

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

“…Large rearrangements were not identified in the BRCA1/2 genes (n=26) in our cohort of AJ individuals testing negative for founder and non-founder point mutations, which is consistent with previous reports (Palma et al 2008;Stadler et al 2010). These data are consistent with prior studies showing that founder mutations continue to account for the vast majority of all mutations in this population and suggest that routine screening for large rearrangements does not seem to be warranted in AJ individuals.…”

Analysis of BRCA1 and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

“…To date, at least 81 different large genomic rearrangements have been found in BRCA1 gene and account for 8%–27% of all BRCA1 mutations. Alternatively Alu sequences are less common in BRCA2 gene, where only few large genomic rearrangements are reported, accounting for 0%–11% of all BRCA2 mutations [19-21]. …”

Reflex Testing for GermlineBRCA1,BRCA2,PALB2, andATMMutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

“…14 No large genomic changes in BRCA1, BRCA2, PALB2, or ATM were identified in our FC Study case series. Consistent with these findings are reports showing absence of large genomic changes in BRCA1, BRCA2, and/or PALB2 in families with breast/ovarian cancer with FC ancestry, 22,42,52,53 AJ ancestry, 54 and ethnically diverse families. 13,41,55,56 Large genomic changes in ATM are also rare.…”

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

“…Large rearrangements were not identified in the BRCA1/2 genes (n=26) in our cohort of AJ individuals testing negative for founder and non-founder point mutations, which is consistent with previous reports (Palma et al 2008;Stadler et al 2010). These data are consistent with prior studies showing that founder mutations continue to account for the vast majority of all mutations in this population and suggest that routine screening for large rearrangements does not seem to be warranted in AJ individuals.…”

Analysis of BRCA1 and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals

“…To date, at least 81 different large genomic rearrangements have been found in BRCA1 gene and account for 8%–27% of all BRCA1 mutations. Alternatively Alu sequences are less common in BRCA2 gene, where only few large genomic rearrangements are reported, accounting for 0%–11% of all BRCA2 mutations [19-21]. …”