ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.655del (p.Glu219fs) (rs786202497)

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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 RCV000165339 SCV000216062 pathogenic Hereditary cancer-predisposing syndrome 2017-06-19 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)
Invitae RCV000545663 SCV000633205 pathogenic Familial cancer of breast 2018-05-18 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 5 of the CHEK2 mRNA (c.655delG), causing a frameshift at codon 219. This creates a premature translational stop signal (p.Glu219Asnfs*16) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657336 SCV000779068 pathogenic not provided 2017-06-02 criteria provided, single submitter clinical testing This deletion of one nucleotide in CHEK2 is denoted c.655delG at the cDNA level and p.Glu219AsnfsX16 (E219NfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGAT[delG]AATA. The deletion causes a frameshift which changes a Glutamic Acid to an Asparagine at codon 219, 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. We consider this variant to be pathogenic.
Academic Department of Medical Genetics, University of Cambridge RCV000165339 SCV000992230 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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