Data from Functional Analysis Identifies Damaging <i>CHEK2</i> Missense Variants Associated with Increased Cancer Risk

• DOI: 10.1158/0008-5472.c.6513927.v1
• Publication Date: 2023-03-31T21:17:37Z
• Authors: Rick A.C.M. Boonen; Wouter W. Wiegant; Nandi Celosse; Bas Vroling; Stephan Heijl; Zsofia Kote-Jarai; Martina Mijuskovic; Simona Cristea; Nienke Solleveld-...; Tom van Wezel; Niko Beerenwinkel; Rosalind Eeles; Peter Devilee; Maaike P.G. Vrees...; Giancarlo Marra; Haico van Attikum
• Keywords: CHEK2; Loss function

&lt;div&gt;Abstract&lt;p&gt;Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (&lt;i&gt;CHEK2)&lt;/i&gt; are at an increased risk for developing breast and other cancers. While truncating &lt;i&gt;CHEK2&lt;/i&gt; known to be pathogenic, interpretation missense uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally clinically. Here we describe a mouse embryonic stem (mES) cell–based system quantitatively determine functional impact 50 human &lt;i&gt;CHEK2&lt;/i&gt;. By assessing activity CHK2 phosphorylate one its main targets, Kap1, &lt;i&gt;Chek2&lt;/i&gt; knockout mES cells, 31 were found impair protein function similar extent as variants, while 9 resulted intermediate defects. Mechanistically, most impaired by causing instability or impairing activation through (auto)phosphorylation. Quantitative results showed that degree dysfunction correlates with cancer. Both damaging group [OR 2.23; 95% confidence interval (CI), 1.62–3.07; &lt;i&gt;P&lt;/i&gt; &lt; 0.0001] (OR 1.63; CI, 1.21–2.20; = 0.0014) associated cancer risk, did not show this association 1.13; 0.87–1.46; 0.378). Finally, &lt;i&gt;CHEK2&lt;/i&gt;, c.486A&gt;G/p.D162G, was also identified, which cosegregated familial prostate Altogether, these assays efficiently reliably identified associate cancer.&lt;/p&gt;Significance:&lt;p&gt;Quantitative assessment consequences identifies may aid clinical management patients carriers.&lt;/p&gt;&lt;/div&gt;