Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000212415 | SCV000149922 | uncertain significance | not provided | 2020-03-10 | criteria provided, single submitter | clinical testing | Observed in an individual with colon cancer (You 2019); Published functional studies demonstrate no damaging effect: normal cell growth after DNA damage (Delimitsou 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30730459, 30851065) |
| Ambry Genetics | RCV000116013 | SCV000184367 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-15 | criteria provided, single submitter | clinical testing | The p.D134H variant (also known as c.400G>C), located in coding exon 2 of the CHEK2 gene, results from a G to C substitution at nucleotide position 400. The aspartic acid at codon 134 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in a patient with colorectal cancer at age 41 that showed proficient MMR protein staining on immunohistochemistry and with a family history meeting Bethesda criteria (You YN et al. Dis Colon Rectum, 2019 04;62:429-437). This alteration has also been reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439), and in at least one subject 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 observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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 | RCV000473822 | SCV000550526 | uncertain significance | Familial cancer of breast | 2024-01-25 | 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 134 of the CHEK2 protein (p.Asp134His). This variant is present in population databases (rs372874441, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30730459). ClinVar contains an entry for this variant (Variation ID: 128072). 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. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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. |
| Mendelics | RCV000473822 | SCV000839493 | uncertain significance | Familial cancer of breast | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002477285 | SCV000896950 | uncertain significance | Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer | 2022-03-03 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000116013 | SCV001349570 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-06 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with histidine at codon 134 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not impact CHEK2 protein function in a growth complementation assay in yeast (PMID: 30851065). This variant has been reported in a few individuals affected with breast cancer (PMID: 28779002, 33471991). This variant has been identified in 6/282722 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. |
| Sema4, |
RCV000116013 | SCV002537428 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-19 | criteria provided, single submitter | curation | |
| MGZ Medical Genetics Center | RCV000473822 | SCV002579849 | uncertain significance | Familial cancer of breast | 2022-02-25 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000473822 | SCV004217576 | uncertain significance | Familial cancer of breast | 2023-09-03 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212415 | SCV004221742 | uncertain significance | not provided | 2022-08-18 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000023 (3/129046 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with colorectal cancer (PMID: 30730459 (2019)) and breast cancer (PMID: 28779002 (2017)), as well as in two breast cancer cases in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast based assay found that this variant had a comparable growth rate to the wild type (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |