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
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.
Ambry Genetics RCV000116036 SCV000183857 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410273 SCV000489710 uncertain significance Familial cancer of breast 2016-11-11 criteria provided, single submitter clinical testing
Invitae RCV000410273 SCV000550462 uncertain significance Familial cancer of breast 2019-12-22 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 observed in individuals affected with prostate cancer or breast cancer (PMID: 12533788, 31050813). ClinVar contains an entry for this variant (Variation ID: 128092). Experimental studies have shown this variant fails to phosphorylate KAP1 in human cells and results in reduced catalytic activity in vitro (PMID: 31050813). However, another study in yeast revealed this change has no effect on yeast strain growth and proliferation in response to DNA damage (PMID: 30851065). The clinical significance of these results is unknown. 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.
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
Color RCV000116036 SCV000684703 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing

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