ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656835 SCV000149893 uncertain significance not provided 2019-10-31 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect: DNA damage response and cell growth comparable to wildtype (Delimitsou 2019); This variant is associated with the following publications: (PMID: 20713355, 17698850, 30851065)
Ambry Genetics RCV000115984 SCV000186773 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing The p.T378I variant (also known as c.1133C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1133. The threonine at codon 378 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is 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.
Invitae RCV000231285 SCV000289645 uncertain significance Familial cancer of breast 2020-10-27 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.
Counsyl RCV000231285 SCV000488585 uncertain significance Familial cancer of breast 2016-05-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115984 SCV000537537 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 378 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Threonine at this position has been shown to be phosphorylated in response to DNA damage stimuli (PMID: 17698850, 20713355). Functional studies have have shown the mutant protein to be functional in DNA damage repair assay in yeast (PMID: 30851065) and to exhibit deficiency in ionizing radiation-induced kinase activity while retaining basal kinase activity (PMID: 20713355). This variant has not been reported in individuals affected with hereditary cancer in the literature but has been reported in unaffected control individuals (PMID: 31206626). This variant has also been identified in 13/250714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656835 SCV000601144 uncertain significance not provided 2019-03-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764376 SCV000895411 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420894 SCV001623332 uncertain significance not specified 2021-04-25 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1133C>T (p.Thr378Ile) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250714 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.00031), allowing no conclusion about variant significance. c.1133C>T has been reported in the literature in unaffected controls and individuals with breast cancer in one study evaluating 1054 BRCA-negative Hispanics with breast cancer (example, Weitzel_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an in vivo yeast based assay comparing growth rates of each strain with positive and negative controls (example, Delimitsou_2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. To our knolwedge none of the submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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