ClinVar Miner

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

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Total submissions: 10
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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 2019-12-31 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 observed 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). 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.
Color RCV000449435 SCV000537565 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-06 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 Insufficient or conflicting evidence;In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000160437 SCV000698771 uncertain significance not specified 2019-10-28 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1336A>G (p.Asn446Asp) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 253306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (7.5e-05 vs 0.00031), allowing no conclusion about variant significance. The variant was reported in breast cancer, colorectal cancer or Non-Hodgkin Lymphoma patients, without strong evidence for causality (Kraus 2016, Havranek 2015, Pearlman 2016), and was also found in healthy controls (Le Calvez-Kelm 2011). 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 has been reported in an internal sample (APC c.4873delC, p.Gln1625fsX25). In an in vivo, yeast based functional assay, the variant was classified as benign (Delimitsou_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114765 SCV000888102 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001147096 SCV001307874 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
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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