Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164415 | SCV000215053 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-06-25 | criteria provided, single submitter | clinical testing | The p.K253E variant (also known as c.757A>G), located in coding exon 5 of the CHEK2 gene, results from an A to G substitution at nucleotide position 757. The lysine at codon 253 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 1/80 Portuguese patients with hereditary breast and/ovarian cancer who had negative BRCA1/2 testing (Pinto P et al. Breast Cancer Res. Treat., 2016 Sep;159:245-56). 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 | RCV000635790 | SCV000757213 | uncertain significance | Familial cancer of breast | 2023-12-08 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 253 of the CHEK2 protein (p.Lys253Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 27553368, 30303537). ClinVar contains an entry for this variant (Variation ID: 185057). 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. 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 |
RCV001753556 | SCV002005895 | uncertain significance | not provided | 2019-08-20 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal and family history of breast and/or ovarian cancer (Pinto 2016); This variant is associated with the following publications: (PMID: 27553368, 30303537) |