ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.231_245CCAAGAACCTGAGGA[1] (p.77_81DQEPE[1]) (rs587780181)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587933 SCV000149919 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing This in-frame deletion of 15 nucleotides in CHEK2 is denoted c.246_260del15 at the cDNA level and p.Asp82_Glu86del (D82_E86del) at the protein level. The surrounding sequence, with the bases that are deleted in brackets, is AGGA[del15]GCCT. This variant, also known as CHEK2 245del15, delP75-E79, and D77_E82del using alternate nomenclature, was observed in two individuals with prostate cancer, in one individual with a history of Lynch syndrome-associated cancer and/or polyps, and in one individual with a pancreatic neuroendocrine tumor (Dong 2003, Bell 2007, Yurgelun 2015, Scarpa 2017). In vitro analysis of CHEK2 c.246_260del15 showed retention of 40-50% of wild-type kinase activity, suggesting partial loss-of-function (Bell 2007). Scarpa et al. (2017) showed significant reduction of kinase activity; however, when normalized to protein expression level, kinase activity was similar to wild-type. This variant was observed at an allele frequency of 0.03% (9/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This deletion is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider CHEK2 Asp82_Glu86del to be a variant of uncertain significance.
Ambry Genetics RCV000116010 SCV000185083 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbSNP, ESP, 1000 Genomes),Deficient protein function in appropriate functional assay(s),Insufficient evidence
Invitae RCV000197398 SCV000254936 uncertain significance Familial cancer of breast 2018-12-18 criteria provided, single submitter clinical testing This sequence change deletes 15 nucleotides from exon 2 of the CHEK2 mRNA (c.246_260del). This leads to the deletion of 5 amino acid residues in the CHEK2 protein (p.Asp82_Glu86del) but otherwise preserves the integrity of the reading frame. While this variant is present in population databases (rs587780181), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with breast cancer, prostate cancer, non-Hodgkin's lymphoma, as well as in an individual who underwent genetic testing for Lynch syndrome (PMID: 28199314, 12533788, 17721994, 11949635, 25980754). This variant is also known as 245del15, del223-237, delP75-E79 and D77–E82del in the literature. ClinVar contains an entry for this variant (Variation ID: 128069). This variant has been reported to affect CHEK2 protein function (PMID: 17721994, 28199314). 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.
Counsyl RCV000197398 SCV000488956 uncertain significance Familial cancer of breast 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212408 SCV000601161 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587933 SCV000698790 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116010 SCV000821998 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587933 SCV000889328 uncertain significance not provided 2019-01-29 criteria provided, single submitter clinical testing
Color RCV000116010 SCV000902674 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212408 SCV000916883 uncertain significance not specified 2017-12-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587933 SCV001153651 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing

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