ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1336A>G (p.Asn446Asp) (rs121908705)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114765 SCV000210989 uncertain significance not provided 2018-09-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1336A>G at the cDNA level, p.Asn446Asp (N446D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has been observed in at least one individual each with breast cancer, rectal cancer, and non-Hodgkin lymphoma, and in one control individual in a case-control breast cancer study (Le Calvez-Kelm 2011, Havranek 2015, Kraus 2016, Pearlman 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). This variant is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Asn446Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196666 SCV000254924 uncertain significance Familial cancer of breast 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 446 of the CHEK2 protein (p.Asn446Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs121908705, ExAC 0.04%). This variant has been reported in individuals affected with non-Hodgkin lymphoma (PMID: 26506619), breast cancer (PMID: 27616075), and rectal cancer (PMID: 27978560, ClinVar contains an entry for this variant (Variation ID: 126909). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Color RCV000449435 SCV000537565 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160437 SCV000601151 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515378 SCV000611452 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000449435 SCV000661698 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000114765 SCV000698771 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1336A>G (p.Asn446Asp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 8/123152 control chromosomes at a frequency of 0.000065, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). The variant was reported in breast, colorectal cancer and Non-Hodgkin Lymphoma patients however, without strong evidence for causality such as co-segregation. To our knowledge, studies assessing the impact the variant may have on the function of the protein have not been published at the time of classification. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114765 SCV000888102 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114765 SCV000148660 not provided not provided no assertion provided not provided

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