ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1096del (p.Ile366fs)

dbSNP: rs1555913941
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657278 SCV000779009 likely pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing This deletion of one nucleotide in CHEK2 is denoted c.1096delA at the cDNA level and p.Ile366LeufsX16 (I366LfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is TTAG[delA]TTAC. The deletion causes a frameshift which changes an Isoleucine to a Leucine at codon 366, and creates a premature stop codon at position 16 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 RCV000706768 SCV000835838 pathogenic Familial cancer of breast 2019-07-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 545757). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile366Leufs*16) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product.
Myriad Genetics, Inc. RCV000706768 SCV004189512 pathogenic Familial cancer of breast 2023-10-19 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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