ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1036C>T (p.Arg346Cys) (rs201206424)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131219 SCV000186171 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131219 SCV000684550 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Counsyl RCV000232903 SCV000786015 uncertain significance Familial cancer of breast 2018-02-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764379 SCV000895414 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212445 SCV000210979 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1036C>T at the cDNA level, p.Arg346Cys (R346C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). A case-control study detected this variant in 3/1313 early-onset breast cancer patients and 0/1123 age-matched controls (Le Calvez-Kelm 2011). In a large meta-analysis, which included Le Calvez-Kelm et al. (2011), evidence of association with breast cancer risk was observed for European women, with an odds ratio (OR) of 3.39 after excluding selected cases; however, the wide confidence interval included 1.0 (Southey 2016). CHEK2 Arg346Cys was observed at an allele frequency of 0.01% (10/111,540) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the Kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Arg346Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232903 SCV000289640 uncertain significance Familial cancer of breast 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 346 of the CHEK2 protein (p.Arg346Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201206424, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 27595995) and prostate cancer (PMID: 27595995). ClinVar contains an entry for this variant (Variation ID: 142222). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000232903 SCV000839468 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing

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