PURPOSE Family studies are an important but underreported source of information for reclassification of variants of uncertain significance (VUS). We evaluated outcomes of a patient-driven framework that offered familial VUS reclassification analysis to any adult with any clinically ascertained VUS from any laboratory in the United States. METHODS With guidance from FindMyVariant.org, participants recruited their own relatives for study participation. We genotyped relatives, calculated quantitative cosegregation likelihood ratios, and evaluated variant classifications using Tavtigian's unified framework for Bayesian analysis with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. We report participation and VUS reclassification rates from the 50 families enrolled for at least one year and reclassification results for 112 variants from the larger 92-family cohort. RESULTS For the 50-family cohort, 6.7 relatives per family were invited to participate and 67% of relatives returned samples for genotyping. Sixty-one percent of VUS were reclassified, 84% of which were classified as benign or likely benign. Genotyping relatives identified a de novo variant, phase variants, and relatives with phenotypes highly specific for or incompatible with specific classifications. CONCLUSIONS Motivated families can contribute to successful VUS reclassification at substantially higher rates than those previously published. Clinical laboratories could consider offering family studies to all patients with VUS.

中文翻译：

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对意义不明的变异进行重新分类的 92 项患者驱动的家庭研究的结果。

目的 家庭研究是一个重要但被低估的信息来源，用于重新分类具有不确定意义的变体 (VUS)。我们评估了患者驱动框架的结果，该框架为来自美国任何实验室的任何临床确定 VUS 的成年人提供家族性 VUS 重新分类分析。方法 在 FindMyVariant.org 的指导下，参与者招募自己的亲属参与研究。我们使用 Tavtigian 的贝叶斯分析统一框架和美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP) 标准对亲属进行基因分型、计算定量共分离似然比并评估变异分类。我们报告了注册至少一年的 50 个家庭的参与和 VUS 重新分类率，以及来自更大的 92 个家庭队列的 112 个变体的重新分类结果。结果 对于 50 个家庭的队列，每个家庭有 6.7 名亲属被邀请参加，67% 的亲属返回样本进行基因分型。61% 的 VUS 被重新分类，其中 84% 被分类为良性或可能为良性。基因分型亲属确定了从头变异、阶段变异和具有高度特异性或与特定分类不相容的表型的亲属。结论 有动力的家庭可以以比以前公布的高得多的比率成功地促进 VUS 重新分类。临床实验室可以考虑为所有 VUS 患者提供家庭研究。