ClinVar Miner

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

dbSNP: rs786202497
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Total submissions: 10
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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 2020-10-16 criteria provided, single submitter clinical testing The c.655delG pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 655, causing a translational frameshift with a predicted alternate stop codon (p.E219Nfs*16). This alteration, designated as NM_001005735 c.784delG, has been reported in a cohort of 460 individuals from 440 families with at least two primary tumors by age 60 years or at least three by 70 years (Whitworth J et al. Am J Hum Genet, 2018 07;103:3-18). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000545663 SCV000633205 pathogenic Familial cancer of breast 2023-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu219Asnfs*16) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185842). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192408 SCV001360503 pathogenic Hereditary breast ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.655delG (p.Glu219AsnfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 230178 control chromosomes (gnomAD). c.655delG has been reported in the literature in an individual affected with multiple primary tumors (Whitworth_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (3x pathogenic, 1x likely pathogenic). Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798587 SCV002043412 likely pathogenic Breast and/or ovarian cancer 2021-03-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000165339 SCV002052338 pathogenic Hereditary cancer-predisposing syndrome 2021-02-01 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 5 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with multiple primary tumor (PMID: 29909963) and prostate cancer (PMID: 32338768). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV000545663 SCV002549768 pathogenic Familial cancer of breast 2021-10-15 criteria provided, single submitter clinical testing CHEK2:c.655del is a deletion of a single nucleotide in exon 5 predicted to encode a frameshift of the mature mRNA with consequent premature termination of protein synthesis at codon 16 of the frameshift, or 234 (CHEK2:p.( Glu219AsnfsTer16)) using NP_009125.1. This is predicted to result in absent CHEK2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun, et al., 2018, PMID:30192042) (PVS1). CHEK2:c.655del (rs786202497) is absent from population databases and is not on record in the control database FLOSSIES (PM2). This variant has been detected in one individual with colorectal polyps and parathyroid cancer, and one individual with prostate cancer (Whitworth et al., 2018, PMID:29909963; Nguyen-Dumont et al., 2020, PMID:32338768). This variant has not been reported in the scientific literature in association with breast cancer.
Myriad Genetics, Inc. RCV000545663 SCV004043292 pathogenic Familial cancer of breast 2023-06-26 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV000545663 SCV004217633 pathogenic Familial cancer of breast 2023-07-13 criteria provided, single submitter clinical testing

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