ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.846+1G>A (rs864622149)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492671 SCV000581176 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000522765 SCV000620566 likely pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.846+1G>A or IVS7+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 7 of the CHEK2 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published inthe literature. Based on the currently available information, we consider CHEK2 c.846+1G>A to be a likely pathogenicvariant.
Invitae RCV000635951 SCV000757379 likely pathogenic Familial cancer of breast 2018-11-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26484312). ClinVar contains an entry for this variant (Variation ID: 428910). 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). 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.
Academic Department of Medical Genetics, University of Cambridge RCV000492671 SCV000992229 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

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