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 The p.P484L variant (also known as c.1451C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1451. The proline at codon 484 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in 1/1303 breast cancer patients and was absent from 1109 healthy controls (p=0.36) (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In addition, this alteration has been detected in a cohort of 122 patients who underwent multi-gene panel testing for hereditary cancer after having previously tested negative for mutations in BRCA1 and BRCA2 (Yadav S et al. Fam. Cancer. 2017 07;16:319-328). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). However, another in vitro kinase assay showed p.P484L to be damaging (Dutil J et al. Sci Rep 2019 11;9(1):17769). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000590757 SCV000210993 uncertain significance not provided 2020-12-23 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history of breast and/or ovarian cancer (Le Calvez-Kelm 2011, Tung 2015, Capriotti 2017, Yadav 2017, Dutil 2019); Published functional studies are conflicting: DNA damage response and cell growth comparable to wildtype in a yeast-based assay (Delimitsou 2019), but reduced stability and decreased kinase activity, with retained autophosphorylation, in a human cell line (Dutil 2019); This variant is associated with the following publications: (PMID: 25186627, 21244692, 26787654, 27878467, 28102005, 31106920, 30851065, 31780696, 32310333, 31742824)
Invitae RCV000206213 SCV000261439 uncertain significance Familial cancer of breast 2020-10-30 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, 31780696). ClinVar contains an entry for this variant (Variation ID: 140938). This variant has been reported to have conflicting data to determine the effect on CHEK2 protein function (PMID: 30851065, 31780696). 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 Health, Inc RCV000129213 SCV000537531 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 484 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has demonstrated this variant to be benign in a yeast-based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 21244692, 31780696; Lovejoy 2018). This variant has also been identified in 22/265184 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212468 SCV000698780 uncertain significance not specified 2020-11-04 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 (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 7.6e-05 in 236006 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.00031), allowing no conclusion about variant significance. c.1451C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Calvez-Kelm_2011, Tung_2014, Yadav_2016, Duhl_2019, Shao_2019), but has also been found in several individuals over age 70 with no history of cancer (FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function, with conflicting results. The variant was classified as benign following assessment in a yeast-based assay (Delimitsou_2019), but was shown to significantly reduce kinase activity when expressed in HEK293T cells (Duhl_2019). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance.

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