ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1526C>T (p.Pro509Leu) (rs587782541)

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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 RCV000131748 SCV000186789 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000212473 SCV000210996 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1526C>T at the cDNA level, p.Pro509Leu (P509L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has been observed in at least one Ashkenazi Jewish individual with prostate cancer (Tischkowitz 2008). Although this variant was observed in large population cohorts, data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Pro509Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469852 SCV000550431 uncertain significance Familial cancer of breast 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 509 of the CHEK2 protein (p.Pro509Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant was reported in an individual affected with prostate cancer (PMID: 18571837). ClinVar contains an entry for this variant (Variation ID: 142554). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000469852 SCV000785814 uncertain significance Familial cancer of breast 2017-12-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212473 SCV000888112 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing
Color RCV000131748 SCV000902940 likely benign Hereditary cancer-predisposing syndrome 2016-03-06 criteria provided, single submitter clinical testing

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