ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.906A>C (p.Glu302Asp) (rs587780190)

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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 RCV000116031 SCV000186812 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000116031 SCV000684694 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing
GeneDx RCV000212438 SCV000149940 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.906A>C at the cDNA level, p.Glu302Asp (E302D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). CHEK2 Glu302Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Glu302Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000116031 SCV000822005 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780183 SCV000917236 uncertain significance not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.906A>C (p.Glu302Asp) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 228952 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (3.5e-05 vs 0.00031), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.906A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000464095 SCV000550513 uncertain significance Familial cancer of breast 2018-11-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 302 of the CHEK2 protein (p.Glu302Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs587780190, ExAC 0.09%). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 128087). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212438 SCV000888127 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing

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