ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.908+2T>G

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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 RCV003172164 SCV003858950 likely pathogenic Hereditary cancer-predisposing syndrome 2022-11-29 criteria provided, single submitter clinical testing The c.908+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 7 in 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV005101108 SCV005837522 likely pathogenic Familial cancer of breast 2024-10-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 cancer (PMID: 31742824). ClinVar contains an entry for this variant (Variation ID: 2452070). 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.

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