Submissions for variant NM_007194.4(CHEK2):c.1033C>G (p.His345Asp)

dbSNP: rs864622537

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482675	SCV000570022	uncertain significance	not provided	2016-04-18	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1033C>G at the cDNA level, p.His345Asp (H345D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 His345Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 His345Asp occurs at a position that is conserved across species and is located in the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 His345Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002395161	SCV002702430	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-28	criteria provided, single submitter	clinical testing	The p.H345D variant (also known as c.1033C>G), located in coding exon 9 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1033. The histidine at codon 345 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.