ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1489G>A (p.Asp497Asn) (rs143965148)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131571 SCV000186575 likely benign Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Invitae RCV000586318 SCV000261208 likely benign not provided 2019-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000586318 SCV000278930 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1489G>A at the cDNA level, p.Asp497Asn (D497N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been reported in at least one individual with endometrial cancer and one with breast cancer (Tung 2015, Ring 2016). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Asp497Asn is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Asp497Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000203702 SCV000488802 uncertain significance Familial cancer of breast 2016-06-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586318 SCV000698783 likely benign not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1489G>A (p.Asp497Asn) variant located in the kinase domain causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 26/112816 (1/4338), predominantly in the Latino cohort, 21/11240 (1/535), which exceeds the estimated maximal expected allele frequency for a pathogenic CHEK2 variant of 1/35211. Therefore, suggesting the variant is a common polymorphism found in population(s) of Latino origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although multiple reputable clinical laboratories cite the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign until additional information becomes available.
Color RCV000131571 SCV000902708 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586318 SCV001134158 uncertain significance not provided 2019-06-12 criteria provided, single submitter clinical testing
Mendelics RCV000203702 SCV001141348 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing

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