ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1169A>C (p.Tyr390Ser) (rs200928781)

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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 RCV000130486 SCV000185355 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-31 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Other data supporting pathogenic classification
Invitae RCV000206869 SCV000260328 uncertain significance Familial cancer of breast 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 390 of the CHEK2 protein (p.Tyr390Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs200928781, ExAC 0.008%). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501). ClinVar contains an entry for this variant (Variation ID: 141818). In an in vitro assay, this variant was shown to disrupt CHEK2 kinase activity (PMID: 25503501). In summary, this variant is a rare missense change that has been shown to disrupt protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000222009 SCV000279574 likely pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1169A>C at the cDNA level, p.Tyr390Ser (Y390S) at the protein level, and results in the change of a Tyrosine to a Serine (TAC>TCC). This variant has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer, and in an in vitro assay, did not exhibit any kinase activity (Desrichard 2011, Maxwell 2015, Pinto 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). This variant is located in the 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, we consider CHEK2 Tyr390Ser to be a likely pathogenic variant.
Color RCV000130486 SCV000689637 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
Counsyl RCV000206869 SCV000786177 uncertain significance Familial cancer of breast 2018-03-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000206869 SCV000919228 likely pathogenic Familial cancer of breast 2018-10-01 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1169A>C (p.Tyr390Ser) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246920 control chromosomes. c.1169A>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, though strong evidence for causality (i.e., cosegregation) was not reported. At least one publication reports experimental evidence evaluating an impact on protein function, where CHEK2 kinase activity was similar to the negative control and the well-characterized 1100delC mutation, all of which were less than 10% of the WT activity (Desrichard_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting classifications (3x - likely pathogenic; 2x - VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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