Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000223114 | SCV000277894 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-14 | criteria provided, single submitter | clinical testing | The p.V451A variant (also known as c.1352T>C), located in coding exon 11 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1352. The valine at codon 451 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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. |
Gene |
RCV000481522 | SCV000570082 | uncertain significance | not provided | 2018-01-29 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1352T>C at the cDNA level, p.Val451Ala (V451A) at the protein level, and results in the change of a Valine to an Alanine (GTC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). CHEK2 Val451Ala is located in the kinase domain (Cai 2009, Roeb 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Val451Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV000223114 | SCV000903123 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-09 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with alanine at codon 451 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CHEK2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Invitae | RCV001343023 | SCV001536979 | uncertain significance | Familial cancer of breast | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 451 of the CHEK2 protein (p.Val451Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 233510). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |