Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000160432 | SCV000210982 | uncertain significance | not provided | 2016-05-16 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1045A>G at the cDNA level, p.Lys349Glu (K349E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Lys349Glu 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 Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Lys349Glu 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 Lys349Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV000557927 | SCV000633086 | uncertain significance | Familial cancer of breast | 2017-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine with glutamic acid at codon 349 of the CHEK2 protein (p.Lys349Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in four individuals affected with triple-negative breast cancer (PMID: 28135048). ClinVar contains an entry for this variant (Variation ID: 182433). This variant is not present in population databases (ExAC no frequency). |
Ambry Genetics | RCV000574744 | SCV000669279 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-03-27 | criteria provided, single submitter | clinical testing | The p.K349E variant (also known as c.1045A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1045. The lysine at codon 349 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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. |