ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1451C>T (p.Pro484Leu) (rs564605612)

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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 RCV000129213 SCV000183963 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129213 SCV000537531 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
Counsyl RCV000206213 SCV000488328 uncertain significance Familial cancer of breast 2016-02-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515218 SCV000611453 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000590757 SCV000210993 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1451C>T at the cDNA level, p.Pro484Leu (P484L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has been observed in at least three individuals with personal or family history of breast and/or ovarian cancer (Le Calvez-Kelm 2011, Tung 2015, Yadav 2017). 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 Pro484Leu is located within 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, it is unclear whether CHEK2 Pro484Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212468 SCV000698780 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1451C>T (p.Pro484Leu) 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 8e-05 in 262372 control chromosomes, which is not higher than the estimated maximal expected allele frequency (0.00031) for a pathogenic variant in CHEK2 causing HBOC. c.1451C>T has been reported in the literature in affected individuals. However, these reports do not provide unequivocal conclusions about an association of the variant with HBOC. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (7 VUS, 1 Likely benign). Based on the evidence outlined above, the variant was classified as a variant of uncertain significance.
Invitae RCV000206213 SCV000261439 uncertain significance Familial cancer of breast 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 484 of the CHEK2 protein (p.Pro484Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs564605612, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with breast cancer (PMID: 21244692, 25186627). ClinVar contains an entry for this variant (Variation ID: 140938). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212468 SCV000601156 uncertain significance not specified 2016-10-05 criteria provided, single submitter clinical testing

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