Submissions for variant NM_007194.4(CHEK2):c.704A>G (p.Lys235Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782419

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131466	SCV000186452	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.K235R variant (also known as c.704A>G), located in coding exon 5 of the CHEK2 gene, results from an A to G substitution at nucleotide position 704. The lysine at codon 235 is replaced by arginine, an amino acid with highly similar properties. Functional assays demonstrate that this alteration is invovled in acetylation of CHK2; p.K235R decreased acetylation of CHK2 and active phospho-CHK2 compared to wildtype, did not elicit the phosporylation of p53, and increased cell survival in response to oxidative distress (Kwon J et al. Exp. Mol. Med., 2019 03;51:1-9; Zhang W et al. Cell Death Differ., 2020 02;27:482-496). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000221976	SCV000279508	uncertain significance	not provided	2015-10-20	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.704A>G at the cDNA level, p.Lys235Arg (K235R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys235Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Lys235Arg occurs at a position that is conserved in mammals and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Lys235Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000692534	SCV000820361	uncertain significance	Familial cancer of breast	2022-11-01	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 142380). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (rs587782419, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 235 of the CHEK2 protein (p.Lys235Arg).
Color Diagnostics, LLC DBA Color Health	RCV000131466	SCV001355161	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-07	criteria provided, single submitter	clinical testing