ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.283C>T (p.Arg95Ter) (rs587781269)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128901 SCV000172762 pathogenic Hereditary cancer-predisposing syndrome 2017-06-30 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 RCV000128901 SCV000911178 pathogenic Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Counsyl RCV000232015 SCV000677767 pathogenic Familial cancer of breast 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000215973 SCV000278920 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted CHEK2 c.283C>T at the cDNA level and p.Arg95Ter (R95X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with breast, prostate, or rectal cancer, and an in vitro functional assay found it to be devoid of kinase activity (Chrisanthar 2008, Le Calvez-Kelm 2011, Knappskog 2016, Raskin 2017). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000232015 SCV000839945 pathogenic Familial cancer of breast 2017-06-05 criteria provided, single submitter clinical testing This c.283C>T (p.Arg95*) variant in the CHEK2 gene has been reported in two patients from Norway with advanced breast cancer [PMID 18725978]. The c.283C>T (p.Arg95*) variant was subsequently detected in 12 individuals from a case control study: 4 from the control group (no cancer), 4 had prostate cancer and 4 had breast cancer [PMID 27708748]. The variant was also detected in a cohort of patients with breast cancer [PMID 21244692]. This c.283C>T creates a stop codon at amino acid position 95 of the CHEK2 protein (p.Arg95*), which is predicted to results in a loss of function of the protein. This variant has been observed in 2 heterozygous individuals in the ExAC population database ( It is thus interpreted as a pathogenic variant
Integrated Genetics/Laboratory Corporation of America RCV000232015 SCV000919212 pathogenic Familial cancer of breast 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.283C>T (p.Arg95X) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 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 (e.g. c.1100delC, p.Thr367fsX15; c.1263delT, p.Ser422fsX15; c.1555C>T, p.Arg519X). One in silico tool predicts a damaging outcome for this variant. One study showed lack of dimerization of this variant with the WT Chk2 protein as well as no kinase activity (Chrisanthar_2008). This variant was found in 6/255878 control chromosomes at a frequency of 0.0000234, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284). This variant was reported in multiple patients with breast, prostate, and colorectal cancer (Knappskog_2016, Calvez-Kelm_2011, Cragun_2014), most frequently in patients of Norwegian descent . In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000232015 SCV000289680 pathogenic Familial cancer of breast 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg95*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587781269, ExAC 0.009%). This variant has been reported in individuals affected with breast cancer (PMID: 18725978, 21244692). It has also been suggested as a variant restricted to the Norwegian population, where it has been observed in individuals affected with prostate and breast cancer, and in unaffected individuals (PMID: 27708748). ClinVar contains an entry for this variant (Variation ID: 140772). Experimental studies have shown that this nonsense change abolishes the kinase activity of the CHEK2 protein (PMID: 18725978). Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000215973 SCV000691837 pathogenic not provided no assertion criteria provided clinical testing

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