ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1337del (p.Asn446fs) (rs876659639)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219411 SCV000276310 pathogenic Hereditary cancer-predisposing syndrome 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000219411 SCV000909475 pathogenic Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing
GeneDx RCV000254757 SCV000322535 likely pathogenic not provided 2016-02-01 criteria provided, single submitter clinical testing This deletion of one nucleotide in CHEK2 is denoted c.1337delA at the cDNA level and p.Asn446ThrfsX23 (N446TfsX23) at the protein level. The normal sequence, with the base that is deleted in braces, is TACA[A]CTTC. The deletion causes a frameshift, which changes an Asparagine to a Threonine at codon 446, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Invitae RCV000547049 SCV000633125 pathogenic Familial cancer of breast 2018-04-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn446Thrfs*23) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254757 SCV000601152 likely pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing

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