Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000568579 | SCV000669295 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-02 | criteria provided, single submitter | clinical testing | The c.401A>G variant (also known as p.D134G), located in coding exon 2 of the CHEK2 gene, results from an A to G substitution at nucleotide position 401. The aspartic acid at codon 134 is replaced by glycine, an amino acid with similar properties. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, as a missense change, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV001248007 | SCV001421466 | uncertain significance | Familial cancer of breast | 2023-03-22 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 483397). 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 aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 134 of the CHEK2 protein (p.Asp134Gly). |
Preventiongenetics, |
RCV003403355 | SCV004104925 | uncertain significance | CHEK2-related condition | 2023-08-13 | criteria provided, single submitter | clinical testing | The CHEK2 c.401A>G variant is predicted to result in the amino acid substitution p.Asp134Gly. This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported as a germline variant in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/483397). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |