ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1375+1G>C

dbSNP: rs759706360
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001011222 SCV001171519 likely pathogenic Hereditary cancer-predisposing syndrome 2023-06-14 criteria provided, single submitter clinical testing The c.1375+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 11 of the CHEK2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 RCV001035082 SCV001198395 likely pathogenic Familial cancer of breast 2019-12-06 criteria provided, single submitter clinical testing 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. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CHEK2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 12 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

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