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遗传性癌症基因中的变异管理和解释：拉丁美洲的机构经验。

Variant curation and interpretation in hereditary cancer genes: An institutional experience in Latin America.

机构信息

Medical Subdirection, Instituto Nacional de Cancerología, Bogotá, Colombia.

Subdirection of Research, Instituto Nacional de Cancerología, Bogotá, Colombia.

出版信息

Mol Genet Genomic Med. 2023 May;11(5):e2141. doi: 10.1002/mgg3.2141. Epub 2023 Mar 10.

DOI:10.1002/mgg3.2141
PMID:36905130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10178801/
Abstract

BACKGROUND

Variant curation refers to the application of evidence-based methods for the interpretation of genetic variants. Significant variability in this process among laboratories affects clinical practice. For admixed Hispanic/Latino populations, underrepresented in genomic databases, the interpretation of genetic variants for cancer risk is challenging.

METHODS

We retrospectively evaluated 601 sequence variants detected in patients participating in the largest Institutional Hereditary Cancer Program in Colombia. VarSome and PathoMAN were used for automated curation, and ACMG/AMP and Sherloc criteria were applied for manual curation.

RESULTS

Regarding the automated curation, 11% of the variants (64/601) were reclassified, 59% (354/601) had no changes in its interpretation, and the other 30% (183/601) presented conflicting interpretations. With respect to manual curation, of the 183 variants with conflicting interpretations, 17% (N = 31) were reclassified, 66% (N = 120) had no changes in their initial interpretation, and 17% (N = 32) remained with conflicting interpretation status. Overall, 91% of the VUS were downgraded and 9% were upgraded.

CONCLUSIONS

Most VUS were reclassified as benign/likely benign. Since false-positive and -negative results can be obtained with automated tools, manual curation should also be used as a complement. Our results contribute to improving cancer risk assessment and management for a broad range of hereditary cancer syndromes in Hispanic/Latino populations.

摘要

背景

变异分析是指应用循证方法对遗传变异进行解释。实验室之间在该过程中的显著差异影响了临床实践。对于在基因组数据库中代表性不足的混合裔西班牙裔/拉丁裔人群，癌症风险遗传变异的解释具有挑战性。

方法

我们回顾性评估了参与哥伦比亚最大机构遗传性癌症计划的患者中检测到的 601 个序列变异。VarSome 和 PathoMAN 用于自动化分析，ACMG/AMP 和 Sherloc 标准用于手动分析。

结果

在自动化分析中，11%（64/601）的变异被重新分类，59%（354/601）的变异解释没有变化，其余 30%（183/601）的变异解释存在冲突。在手动分析中，对于有冲突解释的 183 个变异，17%（N=31）被重新分类，66%（N=120）的初始解释没有变化，17%（N=32）仍然存在冲突解释状态。总体而言，91%的 VUS 被降级，9%被升级。

结论

大多数 VUS 被重新分类为良性/可能良性。由于自动化工具可能会产生假阳性和假阴性结果，因此也应使用手动分析作为补充。我们的结果有助于改善西班牙裔/拉丁裔人群中广泛遗传性癌症综合征的癌症风险评估和管理。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/93855dba0df3/MGG3-11-e2141-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/167076edab10/MGG3-11-e2141-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/27da29ad2ae3/MGG3-11-e2141-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/fe468c1e06ca/MGG3-11-e2141-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/93855dba0df3/MGG3-11-e2141-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/167076edab10/MGG3-11-e2141-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/27da29ad2ae3/MGG3-11-e2141-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/fe468c1e06ca/MGG3-11-e2141-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f5d0/10178801/93855dba0df3/MGG3-11-e2141-g001.jpg

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