ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.319+2T>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV003585125 SCV004361405 likely pathogenic Hereditary cancer-predisposing syndrome 2022-12-05 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the canonical +2 position of intron 2 splice donor site of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with CHEK2-related disorders in the literature. This variant has been identified in 1/250830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same position, c.319+2T>A, is known to be disease-causing (ClinVar variation ID: 142352). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003779356 SCV004676286 likely pathogenic Familial cancer of breast 2023-03-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 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 present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. 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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