意大利创始人 BRCA1 变体 p.His1673del 携带者的非典型癌症风险状况：对分类和临床管理的影响。
Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.
发表日期：2024 Aug
作者：
Giovanni Innella, Cristina Fortuno, Laura Caleca, Bing-Jian Feng, Courtney Carroll, Michael T Parsons, Sara Miccoli, Marco Montagna, Daniele Calistri, Laura Cortesi, Barbara Pasini, Siranoush Manoukian, Daniela Giachino, Laura Matricardi, Maria Cristina Foti, Valentina Zampiga, Claudia Piombino, Elena Barbieri, Francesca Vignolo Lutati, Jacopo Azzolini, Rita Danesi, Valentina Arcangeli, Sandrine M Caputo, Nadia Boutry-Kryza, Vincent Goussot, Susan Hiraki, Marcy Richardson, , Simona Ferrari, Paolo Radice, Amanda B Spurdle, Daniela Turchetti
来源：
Experimental Hematology & Oncology
摘要：
BRCA1:c.5017_5019del (p.His1673del) 是意大利北部相对常见的创始人变体。尽管先前提出了致病性，但公共数据库中的变异分类仍然存在冲突，需要额外的证据。乳腺癌/卵巢癌和其他癌症类型的最大可能性外显率是使用来自 53 个信息丰富的意大利家庭的完整谱系数据估计的。使用基于 GFP 片段重组的 PPI 测定评估该变体对 BRCA1-ABRAXAS1 相互作用的影响。结果与多个来源的附加数据相结合，根据 BRCA1/2 指定的 ACMG/AMP 分类规则对变异进行分类。变异携带者患卵巢癌的风险增加（HR = 33.0，95% CI = 7.0-155.0；累积风险70岁 = 27.6%，95% CI = 12.6-40.0%），但乳腺癌则不然（HR = 0.7，95% CI = 0.2-2.2）。子宫癌风险增加（HR = 8.0，95% CI = 1.03-61.6），需要进一步评估。在标准 BRCA1 乳腺癌和卵巢外显率的假设下，有利于致病性的似然比为 98898642.82，在排除乳腺癌诊断后（基于外显率结果），有利于致病性的似然比为 104240832.84。功能分析表明，该变体废除了 BRCA1-ABRAXAS1 结合，支持 ACMG/AMP 基于规则的模型内的 PS3 代码分配。总的来说，这些发现可以将该变异分类为致病性。 BRCA1:c.5017_5019del(p.His1673del) 的致病性已得到证实；然而，与其他国家的家庭和大多数 BRCA1 致病性变异携带者不同，意大利家庭的乳腺癌风险并未增加。了解该变异和其他变异的非典型风险状况将为基于特定基因型的个性化管理铺平道路。© 2024 作者。约翰·威利出版的癌症医学
BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence.Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1-ABRAXAS1 interaction was assessed using a GFP-fragment reassembly-based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2.Variant-carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0-155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6-40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2-2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03-61.6) emerged, warranting further evaluation. Likelihood-ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1-ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule-based model. Collectively, these findings allowed to classify the variant as pathogenic.Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.