Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.
Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.
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DOI：
10.1136/jmg-2022-108807
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发表时间：
2023-06
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
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CDH 1的生殖系致病性变异与弥漫性胃癌和小叶性乳腺癌的风险增加相关。降低风险的策略包括考虑预防性手术，从而准确解释生殖系CDH 1变异对医生决定这些程序至关重要。临床基因组资源（ClinGen）CDH 1变异体治疗专家小组（VCEP）制定了CDH 1变异体治疗的质量标准，目的是解决意义不确定（VUS）的变异体和与ClinVar相互冲突的解释，并继续更新这些质量标准。根据更新的基因检测临床标准、ClinGen的新建议和正在进行的CDH 1变体治疗的专家知识，修改了CDH 1变体分类质量标准。CDH 1 VCEP使用更新的CDH 1质量标准审查了273种变体，并纳入了诊断实验室提供的已发表和未发表的数据。更新后的CDH 1特定解释指南包括自2018年初始规范以来的11项重大修改。使用改进的指南，97%（36/37）的ClinVar解释冲突的变异被分解为良性、可能良性、可能致病或致病，35%（15/43）的VUS被分解为良性或可能良性。总体而言，88%（239/273）的策划变体具有非VUS分类。迄今为止，已知仅有的被归类为致病性或可能致病性的错义变体会影响剪接，因此，功能研究未被验证可用于解释CDH 1变体。专家小组对CDH 1特异性标准的发展和演变导致对该临床可操作基因中变异的不确定和冲突解释减少，最终导致更有效的临床管理建议。
Germline pathogenic variants in CDH1 are associated with increased risk for diffuse gastric cancer and lobular breast cancer. Risk-reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding upon these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications. CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories. Updated CDH1-specific interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications. To date, the only missense variants classified as pathogenic or likely pathogenic are known to affect splicing and therefore, functional studies are not validated for use in the interpretation of CDH1 variants. The development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene which ultimately leads to more effective clinical management recommendations.
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影响因子：
3.9
作者：
Mester JL;Ghosh R;Pesaran T;Huether R;Karam R;Hruska KS;Costa HA;Lachlan K;Ngeow J;Barnholtz-Sloan J;Sesock K;Hernandez F;Zhang L;Milko L;Plon SE;Hegde M;Eng C
通讯作者：
Eng C
影响因子：
5.3
作者：
Drabkin, HJ;Rajbhandary, UL
通讯作者：
Rajbhandary, UL
DOI：
10.1073/pnas.1207846109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Lee, Sooncheol;Liu, Botao;Qian, Shu-Bing
通讯作者：
Qian, Shu-Bing
影响因子：
3.5
作者：
de la Hoya, Miguel;Soukarieh, Omar;Spurdle, Amanda B.
通讯作者：
Spurdle, Amanda B.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G