RESUMO
Mutations in the BRCA1 and BRCA2 genes increase the risk for various cancers including breast, ovarian, prostate, pancreas and melanoma. Identifying BRCA1/2 mutation carriers enables risk assessment, surveillance, early detection and risk reduction. In certain Israeli sub-populations recurring and founder mutations have been identified and for these, testing for founder mutations is simple, efficient and cost-effective. Founder mutations in the Jewish Ethiopian population have not been described. We report here the identification of a recurring BRCA2 mutation in the Ethiopian Jewish population; c.5159C>A; p.Ser1720Ter, which has only been described once before in this population. In addition, in another family of the same origin we found the BRCA2 c.7579delG; p.Val2527Ter mutation that has been previously described in two different Jewish Ethiopian families. In Israel genetic testing is performed in a sequential stepwise manner, first testing a panel of predominant mutations and if negative further testing by gene sequencing is offered. Recently it has been decided to expand the founder mutation panel to include mutations which have been found in two or more separate families. This new panel will include the BRCA2 c.7579delG; p.Val2527Ter mutation, and we recommend that the BRCA2 c.5159C>A; p.Ser1720Ter mutation should also be added to the new predominant mutation panel.
Assuntos
Genes BRCA2 , Judeus , Proteína BRCA2/genética , Etiópia , Testes Genéticos , Humanos , Judeus/genética , Masculino , MutaçãoAssuntos
Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Efeito Fundador , Judeus/genética , Proteínas de Membrana/genética , Doenças Renais Policísticas/genética , Retinose Pigmentar/genética , Transtornos da Motilidade Ciliar/epidemiologia , Transtornos da Motilidade Ciliar/patologia , Encefalocele/epidemiologia , Encefalocele/patologia , Etiópia/epidemiologia , Feminino , Humanos , Masculino , Doenças Renais Policísticas/epidemiologia , Doenças Renais Policísticas/patologia , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/patologia , Iêmen/epidemiologiaRESUMO
BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer/métodos , Etnicidade/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Etnicidade/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Pessoa de Meia-Idade , Penetrância , Prognóstico , Adulto JovemRESUMO
PURPOSE: BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non-predominant mutations in BRCA1/2 in ethnically diverse high-risk cases. METHODS: Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was ≥ 10%. RESULTS: Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case. CONCLUSIONS: The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high-risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel.
