ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.499G>A (p.Gly167Arg) (rs72552322)

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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 RCV000131700 SCV000186737 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other strong data supporting pathogenic classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212424 SCV000609074 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing
Color RCV000131700 SCV000689693 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000212424 SCV000210963 likely pathogenic not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.499G>A at the cDNA level, p.Gly167Arg (G167R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been reported in female and male breast cancer patients and in individuals with prostate cancer (Dong 2003, Roeb 2012, Dufault 2004, Maxwell 2015, Tung 2015, Tung 2016, Lolas Hamameh 2017, Fostira 2018, Hauke 2018, Wu 2018). In a yeast-based functional assay, CHEK2 Gly167Arg had no response to DNA damage and was defined as damaging (Roeb 2012). Although co-segregation in one breast cancer family was complicated by the observation of this variant in the compound heterozygous state with another CHEK2 variant, the authors suggested that both variants were contributory to cancer risk (Roeb 2012). Furthermore, Roeb et al. (2012) reported that the other CHEK2 variant identified in this family was not as damaging as CHEK2 Gly167Arg with respect to DNA damage response. CHEK2 Gly167Arg 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 Gly167Arg to be a likely pathogenic variant.
GeneKor MSA RCV000131700 SCV000821725 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000200030 SCV000254943 likely pathogenic Familial cancer of breast 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 167 of the CHEK2 protein (p.Gly167Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs72552322, ExAC 0.006%). This variant has been reported to segregate with disease in several families with breast cancer (PMID: 22419737, Invitae). It has also been reported in individuals with breast cancer (PMID: 27616075, 15095295, 25503501, 26976419, 25452411) and sporadic prostate cancer (PMID: 12533788), as well as an unaffected individual with a family history of cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 142524). An experimental study in yeast has shown that this missense change impairs the ability of CHEK2 to support cell growth and respond to DNA damage (PMID: 22419737). 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.
PreventionGenetics RCV000212424 SCV000806883 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212424 SCV000601171 likely pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131700 SCV000886682 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-09 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210071 SCV000266066 likely pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing

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