Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000213717 | SCV000276681 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-23 | criteria provided, single submitter | clinical testing | The p.D409N variant (also known as c.1225G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1225. The aspartic acid at codon 409 is replaced by asparagine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 130000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.D409N remains unclear. |
| Gene |
RCV000220442 | SCV000279774 | uncertain significance | not provided | 2016-01-06 | criteria provided, single submitter | clinical testing | This variant is denoted CHEK2 c.1225G>A at the cDNA level, p.Asp409Asn (D409N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Asp409Asn 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 Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Asp409Asn occurs at a position that is conserved across species and is located in the protein kinase domain (Roeb 2012, UniProt). 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 Asp409Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000526458 | SCV000633112 | uncertain significance | Familial cancer of breast | 2023-02-23 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 409 of the CHEK2 protein (p.Asp409Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34903604). ClinVar contains an entry for this variant (Variation ID: 232524). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 34903604). 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. |