ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.591del (p.Val198fs)

dbSNP: rs587782245
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130949 SCV000185863 pathogenic Hereditary cancer-predisposing syndrome 2024-06-03 criteria provided, single submitter clinical testing The c.591delA pathogenic mutation, located in coding exon 3 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 591, causing a translational frameshift with a predicted alternate stop codon (p.V198Ffs*7). This alteration (designated as 589delA) has been reported in an early-onset breast cancer patient and results in inactivation of CHK2 kinase activity (Bell D et al. Int. J. Cancer. 2007 Dec;121(12):2661-7). It has also been reported in a patient with male breast cancer in his sixties (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000235159 SCV000211013 pathogenic not provided 2023-05-16 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with prostate cancer and breast cancer (Bell et al., 2007; Pritchard et al., 2016; Decker et al., 2017; Pritzlaff et al., 2017; Girard et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 589delA; This variant is associated with the following publications: (PMID: 17721994, 26681312, 27751358, 30303537, 31447099, 27433846, 28008555, 26022348, 28779002, 33803639, 32906215, 32885271, 27806230, 31398194, 34204722, 32805687, 29922827, 28888541, 34687117, 33804961, 30625039, 34308104, 35441217)
Labcorp Genetics (formerly Invitae), Labcorp RCV000204563 SCV000262460 pathogenic Familial cancer of breast 2024-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val198Phefs*7) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs587782245, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 17721994, 26681312, 27433846, 28008555). This variant is also known as 589delA. ClinVar contains an entry for this variant (Variation ID: 142114). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000204563 SCV000488810 likely pathogenic Familial cancer of breast 2016-07-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235159 SCV000601174 pathogenic not provided 2021-08-20 criteria provided, single submitter clinical testing The CHEK2 c.591del (p.Val198Phefs*7) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast or prostate cancer in the published literature (PMID: 32906215 (2020), 30706980 (2019), 28008555 (2017), 27433846 (2016), 26681312 (2015), 26022348 (2015)). The frequency of this variant in the general population, 0.00004 (1/24946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000130949 SCV000684664 pathogenic Hereditary cancer-predisposing syndrome 2022-10-10 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 4 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 17721994, 26681312, 28008555, 30303537) and prostate cancer (PMID: 27433846). This variant has been identified in 6/282716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000235159 SCV000860260 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175504 SCV001339107 pathogenic Hereditary breast ovarian cancer syndrome 2020-03-24 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.591delA (p.Val198PhefsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251334 control chromosomes (gnomAD). c.591delA has been reported in the literature in multiple individuals affected with breast cancer (Bell_2007, Schroeder_2015, Susswein_2016, Girard_2019), male breast cancer (Pritzlaff_2017) and prostate cancer (Pritchard_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and noted that a complete loss-of-function may be presumed for this truncating mutation (Bell_2007). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (6x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000235159 SCV002019284 pathogenic not provided 2019-06-13 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001814065 SCV002061738 pathogenic Familial cancer of breast; Malignant tumor of prostate; Colorectal cancer 2021-11-02 criteria provided, single submitter clinical testing PVS1, PS3, PM2
Sema4, Sema4 RCV000130949 SCV002537619 pathogenic Hereditary cancer-predisposing syndrome 2021-11-08 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000204563 SCV004020225 pathogenic Familial cancer of breast 2023-03-09 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV000204563 SCV004217523 pathogenic Familial cancer of breast 2024-03-24 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492607 SCV004240456 pathogenic Breast and/or ovarian cancer 2023-03-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354068 SCV001548590 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Val198Phefs*7 variant was identified in 4 of 23674 proband chromosomes (frequency: 0.0002) from individuals or families with breast or prostate cancer (Bell 2007, Pritchard 2016, Pritzaff 2016, Susswein 2016). The variant was also identified in dbSNP (ID: rs587782245) as "With Pathogenic allele ", and in ClinVar (classified as pathogenic by Ambry Genetics, GeneDx, Invitae, Color Genomics; as likely pathogenic by Counsil and one clinical laboratory). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.591del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 198 and leads to a premature stop codon at position 204. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV004544296 SCV004784906 pathogenic CHEK2-related disorder 2023-12-20 no assertion criteria provided clinical testing The CHEK2 c.591delA variant is predicted to result in a frameshift and premature protein termination (p.Val198Phefs*7). This variant has been reported to be causative for breast cancer (Schroeder et al. 2015. PubMed ID: 26022348, suppl. Table 1) and for metastatic prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846, Table S1). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142114/). Frameshift variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic.

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