ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1263del (p.Ser422fs) (rs587780174)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212457 SCV000149901 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.1263delT at the cDNA level and p.Ser422ValfsX15 (S422VfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is gCCT[delT]AGTG, where the capital letters are exonic and the lowercase is intronic. The deletion causes a frameshift, which changes a Serine to a Valine at codon 422, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CHEK2 c.1263delT has been reported in individuals with breast cancer and prostate cancer (Le Calvez-Kelm 2011, Mauer 2014, Leongamornlert 2014, Byers 2016, Li 2016, Wu 2018). We consider this variant to be pathogenic.
Ambry Genetics RCV000115992 SCV000172936 pathogenic Hereditary cancer-predisposing syndrome 2017-07-24 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 RCV000198820 SCV000253898 pathogenic Familial cancer of breast 2019-01-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser422Valfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780174, ExAC 0.01%). This variant has been reported in individuals affected with breast, prostate, bladder, colon and urethral cancer (PMID: 21244692, 24113346, 24556621, 26681312). ClinVar contains an entry for this variant (Variation ID: 128053). Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000198820 SCV000488848 pathogenic Familial cancer of breast 2016-07-05 criteria provided, single submitter clinical testing
Color RCV000115992 SCV000684579 pathogenic Hereditary cancer-predisposing syndrome 2014-12-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585980 SCV000698766 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1263delT (p.Ser422Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate protein kinase domain. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory and others (e.g. p.Arg519X, c.1434delA, etc.). This variant was found in 6/117456 control chromosomes at a frequency of 0.0000511, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported in multiple cancer patients including breast and prostate cancer and is classified as pathogenic in literature and by multiple clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212457 SCV000888101 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779367 SCV000915967 likely pathogenic CHEK2-Related Cancer Susceptibility 2018-11-01 criteria provided, single submitter clinical testing The CHEK2 c.1263delT (p.Ser422ValfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser422ValfsTer15 variant has been reported in at least six studies in at least 25 individuals undergoing hereditary cancer testing or diagnosed with various cancer types (La Calvez-Kelm et al. 2011; Leongamornlert et al. 2014; Mauer et al. 2014; Susswein et al. 2015; Byers et al. 2016; Leedom et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants, the p.Ser422ValfsTer15 variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Academic Department of Medical Genetics, University of Cambridge RCV000115992 SCV000992227 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.
True Health Diagnostics RCV000115992 SCV000788000 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing

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