Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000160438 | SCV000210990 | uncertain significance | not provided | 2014-06-19 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1405G>A at the cDNA level, p.Val469Met (V469M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Val469Met was not observed in approximately 3,700 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 Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Val469Met occurs at a position that is highly conserved across species and is located in the protein kinase domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Val469Met is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV001850266 | SCV002171918 | uncertain significance | Familial cancer of breast | 2022-09-20 | 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 182438). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 469 of the CHEK2 protein (p.Val469Met). |