Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222979 | SCV000273669 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-06-07 | criteria provided, single submitter | clinical testing | The p.D470H variant (also known as c.1408G>C), located in coding exon 12 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1408. The aspartic acid at codon 470 is replaced by histidine, an amino acid with similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This alteration was also reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV000463739 | SCV000550470 | uncertain significance | Familial cancer of breast | 2023-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 470 of the CHEK2 protein (p.Asp470His). This variant is not present in population databases (gnomAD no frequency). 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: 230209). 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001284479 | SCV001470302 | uncertain significance | not provided | 2020-02-05 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001284479 | SCV001792132 | uncertain significance | not provided | 2022-01-07 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Hauke 2018); This variant is associated with the following publications: (PMID: 29522266, 22419737, 19782031) |
| Baylor Genetics | RCV000463739 | SCV004217479 | uncertain significance | Familial cancer of breast | 2023-10-26 | criteria provided, single submitter | clinical testing |