ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.980A>G (p.Tyr327Cys) (rs587780194)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116036 SCV000183857 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116036 SCV000684703 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000410273 SCV000489710 uncertain significance Familial cancer of breast 2016-11-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515334 SCV000611457 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212443 SCV000149945 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.980A>G at the cDNA level, p.Tyr327Cys (Y327C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was reported in 1/400 sporadic prostate cancer cases and was not observed in 423 unaffected male controls (Dong 2003). CHEK2 Tyr327Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). CHEK2 Tyr327Cys is located within the protein 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 Tyr327Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000410273 SCV000550462 uncertain significance Familial cancer of breast 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 327 of the CHEK2 protein (p.Tyr327Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587780194, ExAC 0.006%). This variant has been reported in the literature in an individual affected with prostate cancer (PMID: 12533788). ClinVar contains an entry for this variant (Variation ID: 128092). 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.

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