SDHA
直线(几何图形)
计算机科学
生物
遗传学
基因
数学
基因表达
几何学
作者
Jason D. Kent,Lillian R. Klug,Michael C. Heinrich
标识
DOI:10.1158/1078-0432.c.7565505
摘要
<div>AbstractPurpose:<p><i>SDHA</i> mutations are the most common cause of succinate dehydrogenase (SDH)–deficient GIST. Enhanced cancer surveillance of individuals carrying a known pathogenic germline <i>SDHA</i> mutation has the potential to detect early-stage tumors, allowing for improved patient outcomes. However, more than 95% of the >1,000 <i>SDHA</i> missense variants listed in ClinVar are variants of uncertain significance. Our ability to interpret the significance of <i>SDHA</i> variants must improve before genetic sequencing can be utilized to its full potential.</p>Experimental Design:<p><i>SDHA</i> variants were introduced into a clonal <i>SDHA</i>-knockout cell line via Bxb1-mediated recombination. SDH activity and SDHA abundance were determined for each variant, and logistic regression analysis was used to derive functional evidence for clinical variant interpretation.</p>Results:<p>Our analysis revealed that cancer-associated <i>SDHA</i> missense variants can be clearly distinguished from noncancer variants according to the extent of SDH dysfunction caused. As such, SDH activity data can be used to predict cancer pathogenicity with strong performance metrics, exceeding those of computational prediction tools. From these data, we obtained functional evidence for clinical variant interpretation from 21 of 22 assayed variants of uncertain significance, with 19 in favor of cancer pathogenicity and two against pathogenicity. Lastly, simulating the addition of our functional evidence with limited preexisting evidence allowed for 18 of 22 variants to be reclassified.</p>Conclusions:<p>We describe a novel pipeline for investigating the functional consequences of <i>SDHA</i> missense variants. In total, we characterized 72 variants, developed criteria for obtaining functional evidence, and demonstrated the potential of this evidence for clinical variant interpretation.</p></div>
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