ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.433C>T (p.Arg145Trp) (rs137853007)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505730 SCV000149925 likely pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.433C>T at the cDNA level, p.Arg145Trp (R145W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). CHEK2 Arg145Trp was published as a germline variant in a case of neuroblastoma and in an individual with breast cancer from a family with a history of Li Fraumeni-like disease whose tumor demonstrated loss of heterozygosity (Lee 2001b, Pugh 2013). In addition, it has been observed in several hereditary breast cancer families, one of which had co-segregation analysis that showed the variant tracking with cancer (Friedrichsen 2004, Desrichard 2011, Roeb 2012, Caminsky 2016, Thompson 2016). Multiple in vitro and in vivo functional studies have confirmed that this variant results in decreased or absent kinase activity (Falck 2001a, Falck 2001b, Lee 2001a, Wu 2001, Desrichard 2011). In addition, this variant has been shown to have deficient response to DNA damage, increased sensitivity to ionizing radiation, cyclohexamide and lactacystin, and inability to bind to wild type BRCA1 and TP53 (Falck 2001b, Lee 2001a, Lee 2001b, Wu 2001, Li 2002, Kilpivaara 2004, Roeb 2012). CHEK2 Arg145Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FHA domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider CHEK2 Arg145Trp to be a likely pathogenic variant.
Ambry Genetics RCV000116016 SCV000185008 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-14 criteria provided, single submitter clinical testing Other data supporting pathogenic classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Invitae RCV000197612 SCV000253711 likely pathogenic Familial cancer of breast 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 145 of the CHEK2 protein (p.Arg145Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137853007, ExAC 0.009%). This variant has been observed in multiple individuals affected with breast cancer (PMID: 11719428, 15535844, 29356917, 29909963), and was reported to segregate with disease in one family (PMID: 22419737). This variant is also known as c.562C>T (p.Arg188Trp) in the literature. ClinVar contains an entry for this variant (Variation ID: 5592). Experimental studies have shown that this missense change disrupts protein stability (PMID: 11719428, 16982735) and prevents DNA damage induced phosphorylation of CHEK2 and activation of downstream factors (PMID: 11390408, 11298456, 12049740, 11571648, 15239132). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000381571 SCV000437721 likely pathogenic CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing The CHEK2 c.433C>T (p.Arg145Trp) missense variant has been identified in a heterozygous state in seven individuals with various types of cancer, including breast, colon, lung, and Li-Fraumeni syndrome (Bell et al. 1999; Lee et al. 2001; Friedrichsen et al. 2004; Roeb et al. 2012). The p.Arg145Trp variant was absent from 659 controls and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Functional studies in cell lines and yeast cells demonstrated that p.Arg145Trp-CHEK2 protein has a reduced half-life compared with wild type CHEK2 and does not become activated in response to DNA damage (Lee et al. 2001; Falck et al. 2001; Li et al. 2002; Sodha et al. 2006; Roeb et al. 2012). Based on the evidence, the p.Arg145Trp 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.
Counsyl RCV000197612 SCV000489610 likely pathogenic Familial cancer of breast 2016-10-28 criteria provided, single submitter clinical testing
Color RCV000116016 SCV000537624 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587420 SCV000698801 likely pathogenic Li-Fraumeni syndrome 2017-07-24 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.433C>T (p.Arg145Trp) variant involves the alteration of a conserved nucleotide located in the Forkhead-associated (FHA) domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies confirmed that the protein with this variant had a half-life of 30 minutes (Lee_Cancer Res_2001) and lack of CHEK2-mediated response to DNA damage (Roeb_Hum. Mol. Genet._2012). This variant was found in 4/121756 control chromosomes at a frequency of 0.0000329, which is slightly higher than the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this variant may be a benign polymorphism. However, this variant has been reported in multiple breast and lung cancer patients, with familial co-segregation evidence (Roeb_Hum. Mol. Genet._2012, Lee_Cancer Res_2001). Also, another variant, p.R145P has also been reported to associate with prostate cancer (HGMD), suggesting R145 is critical. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
Mendelics RCV000197612 SCV000839492 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000197612 SCV000839946 likely pathogenic Familial cancer of breast 2018-01-30 criteria provided, single submitter clinical testing This c.562C>T (p.Arg188Trp) variant in the CHEK2 gene has been reported in multiple breast cancer patients [PMID: 11719428, 22419737] than that observed as extremely low in general population according to gnomad database. Functional studies showed that this mutant is defective of phosphorylation with significantly reduced kinase activity [PMID: 11053450, 11298456, 11390408, 11571648, 12049740, 22114986]. This variant has been observed for co-segregation with individuals affected by breast/lung cancers in a family with Li-Fraumeni syndrome. Multiple in silico predictions suggest this arginine to tryptophan is deleterious. Based upon above evidences, c.562C>T (p.Arg188Trp) variant in the CHEK2 gene is classified as likely pathogenic.
Academic Department of Medical Genetics, University of Cambridge RCV000116016 SCV000992231 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505730 SCV001134168 likely pathogenic not provided 2019-02-22 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Moderate co-segregation with disease in affected and unaffected individuals, but from a single family.
OMIM RCV000005940 SCV000026122 pathogenic Li-Fraumeni syndrome 2 2001-11-15 no assertion criteria provided literature only
ITMI RCV000120554 SCV000084708 not provided not specified 2013-09-19 no assertion provided reference population

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