Richardson Marcy E, Holdren Megan, Brannan Terra, de la Hoya Miguel, Spurdle Amanda B, Tavtigian Sean V, Young Colin C, Zec Lauren, Hiraki Susan, Anderson Michael J, Walker Logan C, McNulty Shannon, Turnbull Clare, Tischkowitz Marc, Schon Katherine, Slavin Thomas, Foulkes William D, Cline Melissa, Monteiro Alvaro N, Pesaran Tina, Couch Fergus J
Ambry Genetics, Aliso Viejo, CA, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
medRxiv. 2024 May 29:2024.05.28.24307502. doi: 10.1101/2024.05.28.24307502.
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated () gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for were modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33 variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar and reevaluation with the VCEP's -specific rules resulted in four that were classified as benign, one as likely pathogenic and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 the 33 pilot variants were not VUS leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in .
临床基因组学（ClinGen）遗传性乳腺癌、卵巢癌和胰腺癌（HBOP）变异评估专家小组（VCEP）由临床遗传学、分子生物学和变异解读领域的国际知名专家组成。该VCEP根据美国食品药品监督管理局（FDA）批准的ClinGen方案，对共济失调毛细血管扩张突变（ATM）基因的美国医学遗传学与基因组学学会/分子病理学协会（ACMG/AMP）指南做出了规范。这些针对ATM的基因特异性规则是在ACMG/AMP指南基础上修改而来，并在一个试点评估阶段针对33个不同类型和分类的ATM变异进行了测试。试点结果显示，HBOP VCEP的分类与ClinVar中收录的分类大部分一致。有6个试点变异在ClinVar中的解读存在冲突，经VCEP的ATM特异性规则重新评估后，VCEP将其中4个分类为良性，1个分类为可能致病，1个分类为意义未明变异（VUS），提高了公共领域变异解读的确定性。总体而言，33个试点变异中有28个不是VUS，分类率达到85%。ClinGen批准的这些修改后的规则显示出对提高ATM变异解读的价值。
