背景：Ashkenazi犹太血统的个体被认为患有特定罕见慢性疾病易感性相关病理变异的患病率较高。在墨西哥，Ashkenazi犹太人中罕见癌症易感遗传变异的患病率和组成尚未得到评估。 目的和方法：我们旨在通过大规模并行测序在341名来自墨西哥Ashkenazi社区的女性中评估病理性变异的患病率。这些受试者通过ALMA癌症重建基金会获得邀请参与研究。提供了术前和术后遗传咨询，并进行了个人、妇产科、人口统计和生活方式变量的问卷调查。从外周血DNA中，对包括21个临床相关基因在内的一个143个癌症易感性基因组成的基因组进行测序。还对墨西哥创始突变BRCA1ex9-12del[NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del]进行了评估。 结果：在研究参与者中（平均年龄±标准差：47±14），有15%的人报告了个人癌症史（50/341）。 14％的参与者（48/341）是携带有病理性和可能病理性变异的高危基因（APC，CHEK2，MSH2，BMPR1A，MEN1，MLH1和MSH6）的携带者，而18.2％（62/341）的基因携带者有不确定临床意义的变异，这些变异与乳腺癌和卵巢癌易感性有关（包含有VUS的基因列表）。在与癌症风险存在模糊或非良好建立的16个易感基因中检测到了17.6％（60/341）的参与者携带病理性和可能是病理性的变异。64％的参与者报告目前饮酒，而墨西哥女性酗酒的患病率为39％。没有任何参与者携带BRCA1或BRCA2的Ashkenazi和墨西哥创始人突变，但是有2％（7/341）的参与者携带了BLM的病理性Ashkenazi犹太创始人基因型。 结论：我们的发现表明，在墨西哥Ashkenazi血统的受试者中，病理变异的组成多样化，符合高危人群的特征，需要进一步研究以充分评估遗传性乳腺癌的负担，并实施适当的预防措施。版权所有©2023 Díaz-Velásquez，Gitler，Antoniano，Kershenovich Sefchovich，De La Cruz-Montoya，Martínez-Gregorio，Rojas-Jiménez，Cortez Cardoso Penha，Terrazas，Wegman-Ostrosky，Levi-Lahad，Zabaleta，Perdomo和Vaca-Paniagua。

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.Copyright © 2023 Díaz-Velásquez, Gitler, Antoniano, Kershenovich Sefchovich, De La Cruz-Montoya, Martínez-Gregorio, Rojas-Jiménez, Cortez Cardoso Penha, Terrazas, Wegman-Ostrosky, Levi-Lahad, Zabaleta, Perdomo and Vaca-Paniagua.