Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561314 | SCV000669268 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-21 | criteria provided, single submitter | clinical testing | The p.G176R variant (also known as c.526G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 526. The glycine at codon 176 is replaced by arginine, an amino acid with dissimilar 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000687272 | SCV000814831 | uncertain significance | Familial cancer of breast | 2022-07-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 176 of the CHEK2 protein (p.Gly176Arg). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 483378). 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). |
| Color Diagnostics, |
RCV000561314 | SCV000912698 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-05 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 176 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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. |