Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478951 | SCV000571996 | uncertain significance | not provided | 2016-10-14 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1610C>T at the cDNA level, p.Ala537Val (A537V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ala537Val was not observed in approximately 3,700 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Ala537Val occurs at a position that is not conserved and is not located in a known functional domain (Roeb 2012). 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 Ala537Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Ambry Genetics | RCV001012412 | SCV001172854 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-12-18 | criteria provided, single submitter | clinical testing | The p.A537V variant (also known as c.1610C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1610. The alanine at codon 537 is replaced by valine, 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. |
Invitae | RCV002525912 | SCV003027460 | uncertain significance | Familial cancer of breast | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 537 of the CHEK2 protein (p.Ala537Val). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 422506). 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). |