Total submissions: 5
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, |
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. |
RCV000114767 | SCV000148662 | not provided | not provided | no assertion provided | not provided |