Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001025506 | SCV001187706 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-09-04 | criteria provided, single submitter | clinical testing | The p.M222K variant (also known as c.665T>A), located in coding exon 4 of the CHEK2 gene, results from a T to A substitution at nucleotide position 665. The methionine at codon 222 is replaced by lysine, 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 | RCV001365086 | SCV001561321 | uncertain significance | Familial cancer of breast | 2020-08-23 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 826538). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 222 of the CHEK2 protein (p.Met222Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. 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. |
| Gene |
RCV001759916 | SCV002008810 | uncertain significance | not provided | 2019-08-11 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Baylor Genetics | RCV001832360 | SCV002096990 | uncertain significance | Li-Fraumeni syndrome 2 | 2022-02-03 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |