Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000460064 | SCV000550544 | uncertain significance | Familial cancer of breast | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 159 of the CHEK2 protein (p.Tyr159Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410058). 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. |
| Color Diagnostics, |
RCV000580089 | SCV000684647 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-28 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 159 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 hereditary cancer in the literature. This variant has been identified in 1/251416 chromosomes 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985702 | SCV001134169 | uncertain significance | not provided | 2021-07-29 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000580089 | SCV001184824 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-01 | criteria provided, single submitter | clinical testing | The p.Y159C variant (also known as c.476A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 476. The tyrosine at codon 159 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741).This variant was also identified in a cohort of 3579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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. |