ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.593-1G>T

dbSNP: rs786203229
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195929 SCV000253713 likely pathogenic Familial cancer of breast 2024-01-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast, prostate, or colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). ClinVar contains an entry for this variant (Variation ID: 216003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000566129 SCV000666386 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing The c.593-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Counsyl RCV000195929 SCV000677829 likely pathogenic Familial cancer of breast 2017-04-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000566129 SCV000689703 likely pathogenic Hereditary cancer-predisposing syndrome 2023-10-02 criteria provided, single submitter clinical testing This variant causes a G>T nucleotide substitution at the -1 position of intron 4 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast, endometrial, prostate, and colorectal cancer (PMID: 25186627, 29659569, 32522261, 32906215). This variant has not been identified 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 Likely Pathogenic.
Mendelics RCV000195929 SCV000839483 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000566129 SCV002537624 likely pathogenic Hereditary cancer-predisposing syndrome 2022-01-04 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002485316 SCV002792970 pathogenic Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer 2022-04-14 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000195929 SCV004020087 likely pathogenic Familial cancer of breast 2023-03-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics RCV000195929 SCV004217659 likely pathogenic Familial cancer of breast 2023-06-14 criteria provided, single submitter clinical testing

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