ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile) (rs587780167)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115984 SCV000186773 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115984 SCV000537537 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Counsyl RCV000231285 SCV000488585 uncertain significance Familial cancer of breast 2016-05-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764376 SCV000895411 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656835 SCV000149893 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1133C>T at the cDNA level, p.Thr378Ile (T378I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). Phosphorylation of Thr378 has been shown to be necessary for appropriate response to DNA damage (Guo 2010, Gupta 2007). This particular variant, however, has not been functionally interrogated to our knowledge. 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). CHEK2 Thr378Ile is located in the kinase domain (Cai 2009, Roeb 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, it is unclear whether CHEK2 Thr378Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000231285 SCV000289645 uncertain significance Familial cancer of breast 2018-09-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 378 of the CHEK2 protein (p.Thr378Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587780167, ExAC 0.02%). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 128046). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212451 SCV000601144 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing

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