ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1215C>A (p.Asn405Lys) (rs587780171)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115989 SCV000149898 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1215C>A at the cDNA level, p.Asn405Lys (N405K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant was observed in an individual with both primary breast and colon cancers, in 1/13,087 breast cancer cases and 0/5,488 controls, and in an individual with familial colorectal cancer (Brinkman 2006, Decker 2017, DeRycke 2017). Although this variant was observed in large population cohorts (Lek 2016), data in this region of CHEK2 are not considered reliable due to high pseudogene homology. 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 Asn405Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000199599 SCV000254920 uncertain significance Familial cancer of breast 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 405 of the CHEK2 protein (p.Asn405Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs587780171, ExAC 0.02%). This variant has been reported in an individual affected with breast and/or colon cancer (PMID: 17100999, 28779002). ClinVar contains an entry for this variant (Variation ID: 128050). 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 and their clinical significance is uncertain. 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.
Ambry Genetics RCV000219945 SCV000273093 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-02 criteria provided, single submitter clinical testing The p.N405K variant (also known as c.1215C>A), located in coding exon 10 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1215. The asparagine at codon 405 is replaced by lysine, an amino acid with similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration has been previously identified in an individual with breast and colon cancer (Brinkman H et al. Clin. Genet. 2006 Dec;70:526-9) and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000199599 SCV000785786 uncertain significance Familial cancer of breast 2017-12-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000115989 SCV000806863 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115989 SCV000888100 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764373 SCV000895408 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000219945 SCV000903066 likely benign Hereditary cancer-predisposing syndrome 2015-12-29 criteria provided, single submitter clinical testing

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