ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1201A>G (p.Thr401Ala) (rs121908704)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114764 SCV000149897 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1201A>G at the cDNA level, p.Thr401Ala (T401A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant was observed in the germline of at least one individual with a personal history of non-Hodgkin lymphoma (Havranek 2015). CHEK2 Thr401Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Thr401Ala occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Thr401Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115988 SCV000216637 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000232135 SCV000289654 uncertain significance Familial cancer of breast 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 401 of the CHEK2 protein (p.Thr401Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs121908704, ExAC 0.002%). This variant has been observed in an individual with Non-Hodgkin lymphoma and an individual with breast cancer (PMID: 26506619, 30851065). ClinVar contains an entry for this variant (Variation ID: 126908). This variant has been reported to have conflicting or insufficient data to determine the effect on 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 RCV000115988 SCV000689639 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Counsyl RCV000232135 SCV000785056 uncertain significance Familial cancer of breast 2017-03-28 criteria provided, single submitter clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114764 SCV000148659 not provided not provided no assertion provided not provided

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