Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.
Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.
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DOI：
10.1002/humu.23640
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发表时间：
2018-11
期刊：
影响因子：
3.9
通讯作者：
Plon SE
中科院分区：
文献类型：
--
作者：
Walsh MF;Ritter DI;Kesserwan C;Sonkin D;Chakravarty D;Chao E;Ghosh R;Kemel Y;Wu G;Lee K;Kulkarni S;Hedges D;Mandelker D;Ceyhan-Birsoy O;Luo M;Drazer M;Zhang L;Offit K;Plon SE
在其关于序列变异解释的标准和指南的里程碑式论文中，美国医学遗传学和基因组学学院（ACMG）和分子病理学协会（AMP）没有解决如何在评估生殖系变异的致病性时使用肿瘤数据。临床基因组资源（ClinGen）建立了一个多学科的工作组，生殖细胞/体细胞变异小组委员会（GSVS）的重点。GSVS实施了一项调查，以确定在对癌症易感基因中的生殖系变异进行分类时整合体细胞数据的现行做法。GSVS随后审查并分析了相关体细胞数据的可用资源，并进行了综合生殖系变异管理练习。该委员会确定，体细胞热点可以系统地整合到中等致病性（PM 1）的证据。显示剪接改变的肿瘤RNA测序数据可被视为支持生殖系致病性（PVS 1）的有力证据，肿瘤表型特征（如突变特征）可被视为支持致病性的证据（PP 4）。然而，目前，体细胞数据，如局灶性杂合性丢失和发生在替代等位基因上的突变，不建议进行系统整合，相反，这类数据的整合应在多学科癌症中心肿瘤正常测序板的指导下进行。
In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes. The GSVS then reviewed and analyzed available resources of relevant somatic data, and performed integrative germline variant curation exercises. The committee determined that somatic hotspots could be systematically integrated into moderate evidence of pathogenicity (PM1). Tumor RNA sequencing data showing altered splicing may be considered as strong evidence in support of germline pathogenicity (PVS1) and tumor phenotypic features such as mutational signatures be considered supporting evidence of pathogenicity (PP4). However, at present, somatic data such as focal loss of heterozygosity and mutations occurring on the alternative allele are not recommended to be systematically integrated, instead, incorporation of this type of data should take place under the advisement of multidisciplinary cancer center tumor-normal sequencing boards.
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