ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1259+1G>C

dbSNP: rs121908707
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566906 SCV000661796 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing The c.1259+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 10 of the CHEK2 gene. This alteration has been reported in the germline of an individual diagnosed with non-Hodgkin lymphoma and mRNA sequencing demonstrated that the donor splice site is abolished, causing exon skipping and premature termination (Havranek O et al. PLoS ONE, 2015 Oct;10:e0140819). 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 donor 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.
Invitae RCV000816882 SCV000957409 pathogenic Familial cancer of breast 2018-12-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID:26506619). This variant has been observed in an individual affected with non-Hodgkin lymphoma (PMID: 26506619). ClinVar contains an entry for this variant (Variation ID: 126911). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Myriad Genetics, Inc. RCV000816882 SCV004043519 likely pathogenic Familial cancer of breast 2023-06-28 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 RCV000816882 SCV004217697 likely pathogenic Familial cancer of breast 2023-03-10 criteria provided, single submitter clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114767 SCV000148662 not provided not provided no assertion provided not provided

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