Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212472 | SCV000149913 | uncertain significance | not provided | 2021-07-14 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intermediate to normal activity with respect to DNA damage response and kinase activity (Delimitsou 2019, Kleiblova 2019); Observed in individuals with breast, ovarian, prostate, and other cancers (Tischkowitz 2008, Yurgelun 2015, Castellanos 2017, Kleiblova 2019); This variant is associated with the following publications: (PMID: 32906215, 27535533, 31050813, 31422574, 30851065, 29596542, 28420421, 28051113, 18571837, 25980754) |
Ambry Genetics | RCV000116004 | SCV000186790 | likely benign | Hereditary cancer-predisposing syndrome | 2024-03-05 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Labcorp Genetics |
RCV000200569 | SCV000254929 | uncertain significance | Familial cancer of breast | 2024-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the CHEK2 protein (p.Pro509Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, Lynch syndrome, ovarian cancer, prostate cancer, skin cancer, and/or uterine cancer (PMID: 18571837, 25980754, 28051113, 29596542, 31050813). ClinVar contains an entry for this variant (Variation ID: 128063). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31409080). 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. |
Counsyl | RCV000200569 | SCV000488484 | uncertain significance | Familial cancer of breast | 2016-04-14 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004528805 | SCV000806873 | uncertain significance | CHEK2-related disorder | 2022-08-23 | criteria provided, single submitter | clinical testing | The CHEK2 c.1525C>T variant is predicted to result in the amino acid substitution p.Pro509Ser. This variant was reported in a patient with prostate cancer of Ashkenazi Jewish origin (Tischkowitz et al. 2008, PubMed ID: 18571837) and also in two individuals with suspected Lynch syndrome (Yurgelun et al. 2015, Supplemental Table 2, PubMed ID: 25980754). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29085140-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128063/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Mendelics | RCV000200569 | SCV000839453 | uncertain significance | Familial cancer of breast | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212472 | SCV000888111 | uncertain significance | not provided | 2024-07-12 | criteria provided, single submitter | clinical testing | The CHEK2 c.1525C>T (p.Pro509Ser) variant has been reported in the published literature in individuals with prostate cancer (PMID: 18571837 (2008)), breast cancer (PMID: 28051113 (2017), PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)), uterine cancer (PMID: 28051113 (2017)), colorectal cancer (PMID: 29596542 (2018)), suspected Lynch syndrome (PMID: 25980754 (2015)), and suspected hereditary cancer (PMID: 32906215 (2020)). This variant has also been reported in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). Functional studies reported conflicting results of this variant's effect on CHEK2 function (PMID: 30851065 (2019), 31050813 (2019), 34903604 (2021), 37449874 (2023)). The frequency of this variant in the general population, 0.0002 (3/15176 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
Fulgent Genetics, |
RCV000764368 | SCV000895403 | uncertain significance | Familial cancer of breast; CHEK2-related cancer predisposition; Bone osteosarcoma; Prostate cancer | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000116004 | SCV000902768 | likely benign | Hereditary cancer-predisposing syndrome | 2016-03-03 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781300 | SCV000919219 | uncertain significance | not specified | 2024-08-01 | criteria provided, single submitter | clinical testing | Variant summary: CHEK2 c.1525C>T (p.Pro509Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 233628 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.1e-05 vs 0.00031), allowing no conclusion about variant significance. c.1525C>T has been reported in the literature in individuals affected with breast cancer, prostate cancer, Lynch syndrome, and other cancers (e.g. Castellanos_2015, Lu_2016, Yurgelun_2015, Tischowitz_2008, Nunziato_2022, Vargas-Parra_2020, Boonen_2022), although it has also been reported in healthy individuals (e.g. Kraemer_2019, Boonen_2022, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or other CHEK2-related cancers. Several publications report experimental evidence evaluating an impact on protein function. A yeast-based DNA-damage assay indicated an intermediate functionality for the variant (Delimitsou_2019), whereas studies in Chek2 knockout mouse embryonic stem cells and in human RPE1-CHEK2-knockout cells found no damaging effect of the variant on its ability to phosphorylate its downstream target KAP1 (Boonen_2022, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 28051113, 30851065, 31422574, 27023146, 26644315, 18571837, 25980754, 37449874, 36035419, 32906215, 34903604). ClinVar contains an entry for this variant (Variation ID: 128063). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
Sema4, |
RCV000116004 | SCV002537390 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-16 | criteria provided, single submitter | curation | |
Ce |
RCV000212472 | SCV004011385 | uncertain significance | not provided | 2023-04-01 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000200569 | SCV004020209 | likely benign | Familial cancer of breast | 2023-03-09 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. |
Fulgent Genetics, |
RCV005025184 | SCV005661007 | uncertain significance | CHEK2-related cancer predisposition; Bone osteosarcoma; Familial prostate cancer | 2024-02-29 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV000781300 | SCV005872379 | uncertain significance | not specified | 2025-03-04 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV005359096 | SCV005912001 | uncertain significance | Li-Fraumeni syndrome; Hereditary breast ovarian cancer syndrome; Familial colorectal cancer type X | 2024-01-15 | criteria provided, single submitter | clinical testing | |
Genome |
RCV003483482 | SCV004228516 | not provided | Familial cancer of breast; Prostate cancer; Colorectal cancer | no assertion provided | phenotyping only | Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. |