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 2019-03-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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.
Invitae RCV000206213 SCV000261439 uncertain significance Familial cancer of breast 2019-12-31 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). This variant has been reported not to substantially affect CHEK2 protein function (PMID: 30851065). 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 RCV000206213 SCV000488328 uncertain significance Familial cancer of breast 2016-02-26 criteria provided, single submitter clinical testing
Color RCV000129213 SCV000537531 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590757 SCV000601156 uncertain significance not provided 2019-06-24 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
Integrated Genetics/Laboratory Corporation of America RCV000212468 SCV000698780 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: The variant, CHEK2 c.1451C>T (p.Pro484Leu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) 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 (gnomAD and Calvez-Kelm 2011). This frequency is not higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (8e-05 vs 0.00031), allowing no conclusion about variant significance. In addition, the variant was also reported in 2 / 7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). The variant, c.1451C>T has been reported in the literature in individuals affected with breast cancers (Calvez-Kelm 2011, Tung 2014, Young 2016, Yadav 2016). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another likely pathogenic variant have been reported (CHEK2 c.1376_1461del (i.e. exon 13 del), in an internal sample), in the same patient supporting evidence for a benign role for this particular variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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