ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.480_482AGA[1] (p.Glu161del) (rs587782008)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130429 SCV000185293 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Deficient protein function in appropriate functional assay(s),Insufficient evidence
GeneDx RCV000212423 SCV000211012 likely pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in CHEK2 is denoted c.483_485delAGA at the cDNA level and p.Glu161del (E161del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGA[delAGA]TCAC. This variant has been observed in several individuals with a personal and family history of breast cancer and was absent in unaffected controls (Sodha 2002, Desrichard 2011, Caminsky 2016, Shirts 2016). Functional studies led to the conclusion that CHEK2 Glu161del was likely pathogenic based on absent kinase activity, reduced protein expression and stability, and reduced activation in response to DNA damage (Sodha 2006, Desrichard 2011). CHEK2 Glu161del was not observed at significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Glutamic Acid amino acid is located in the FHA 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 Glu161del to be likely pathogenic.
Invitae RCV000198423 SCV000255306 uncertain significance Familial cancer of breast 2018-12-28 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 4 of the CHEK2 mRNA (c.483_485delAGA). This leads to the deletion of 1 amino acid residue in the CHEK2 protein (p.Glu161del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782008, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer, although it was absent from the tumors of affected family members (PMID: 12442270). It was also observed in two other individuals affected with breast and/or ovarian cancer (PMID: 26845104, 26898890). This variant is also known as 481_483del in the literature. ClinVar contains an entry for this variant (Variation ID: 141783). Experimental studies have shown that this missense change reduces CHEK2 stability, DNA damage-induced phosphorylation, and kinase activity in vitro (PMID: 16982735, 22114986). In summary, this variant is a rare in-frame deletion of one amino acid that has been observed in affected individuals and disrupts CHEK2 activity in vitro. However, it is unclear whether or not this variant segregates with disease and the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000210175 SCV000266065 likely pathogenic Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000198423 SCV000489121 uncertain significance Familial cancer of breast 2016-08-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212423 SCV000698807 uncertain significance not provided 2016-07-10 criteria provided, single submitter clinical testing Variant summary: The c.483_485delAGA (p.Glu161del) in CHEK2 gene is an in-frame deletion leading to removal of a single Glutamic Acid residue in a region that is conserved across species and is located in the FHA domain. Functional studies have shown that this in-frame deletion reduces CHEK2 stability, DNA damage-induced phosphorylation and significantly diminish kinase activity in vitro. The variant is present in control dataset of ExAC at a low frequency of 0.000016 (2/122994 chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.000028). The variant was identified in at least 3 affected individuals (BRCA1/2 and TP53 mutation free. For 2 of these individuals with personal and family history of BrC segregation analysis was not performed and in 1 LFS family 2 affected individuals did not carry the variant, raising the question about pathogenicity of the variant of interest. The variant of interest has been reported as Likely Pathogenic/VUS by reputable databases/clinical laboratories. Additional clinical, segregation and population data needed to classify this variant with confidence. Taking together, based on the results of the functional studies, the variant was classified as VUS-Possibly Pathogenic.
PreventionGenetics,PreventionGenetics RCV000212423 SCV000806882 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212423 SCV000889336 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Color RCV000130429 SCV000903081 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing
Dr. Peter K. Rogan Lab,Western University RCV000416789 SCV000262585 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-22 no assertion criteria provided research Sequenced patient with familial breast cancer

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