ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.215A>G (p.Tyr72Cys) (rs769819013)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213236 SCV000278241 likely benign Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000318548 SCV000329276 uncertain significance not provided 2016-04-19 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.215A>G at the cDNA level, p.Tyr72Cys (Y72C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Tyr72Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Tyr72Cys occurs at a position that is not conserved and is located in the SQ/TQ domain (Desrichard 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether CHEK2 Tyr72Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475066 SCV000550492 uncertain significance Familial cancer of breast 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 72 of the CHEK2 protein (p.Tyr72Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs769819013, ExAC 0.02%) but has not been reported in the literature in individuals with a CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 233790). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000213236 SCV000904458 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing

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