ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1525C>T (p.Pro509Ser)

gnomAD frequency: 0.00014  dbSNP: rs587780179
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 (formerly Invitae), Labcorp 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
PreventionGenetics, part of Exact Sciences 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, 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, LLC DBA Color Health 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, LabCorp 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, Sema4 RCV000116004 SCV002537390 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-16 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000212472 SCV004011385 uncertain significance not provided 2023-04-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. 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, 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, Rigshospitalet, Copenhagen University Hospital RCV000781300 SCV005872379 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System 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
GenomeConnect - Invitae Patient Insights Network 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.

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