ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs587780167
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656835 SCV000149893 uncertain significance not provided 2023-06-07 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and in unaffected controls (Weitzel et al., 2019; Dorling et al., 2021; Helgadottir et al., 2021); Published functional studies suggest no damaging effect: DNA damage response and cell growth comparable to wild type in yeast-based assays (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 20713355, 17698850, 33471991, 22419737, 19782031, 34282249, 30851065, 31206626)
Ambry Genetics RCV000115984 SCV000186773 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-20 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 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 amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 378 of the CHEK2 protein (p.Thr378Ile). This variant is present in population databases (rs587780167, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 34282249). ClinVar contains an entry for this variant (Variation ID: 128046). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CHEK2 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.
Counsyl RCV000231285 SCV000488585 uncertain significance Familial cancer of breast 2016-05-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115984 SCV000537537 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 378 in the kinase domain of the CHEK2 protein. The reference threonine residue has been shown to be phosphorylated in response to DNA damage stimuli (PMID: 17698850, 20713355) and to play a role in regulating ionizing radiation-induced kinase activity (PMID: 20713355). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to be functional in DNA damage repair assay in yeast (PMID: 30851065). In a large breast cancer case-control study, this variant was observed in 9/60466 cases and 7/53461 unaffected controls (OR=1.137, 95%CI 0.423 to 3.053, p-value=1) (PMID: 33471991, Leiden Open Variation Database DB-ID CHEK2_000355). This variant has 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 2022-10-04 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00012 (4/34568 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in individuals affected with breast cancer and unaffected controls (PMIDs: 30851065 (2019) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast-based functional study has indicated that this variant maintains CHEK2 protein function (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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 likely benign not specified 2023-06-20 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 in GnomAD. 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 (example, Weitzel_2019, Dorling_2021/LOVD database). The results showed that this variant is not associated with breast cancer. Co-occurrence with a pathogenic variant has been reported (BRIP1 c.2108delinsTCC, p.Lys703Ilefs*3 in Helgadottir_2021), providing supporting evidence for a benign role. 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). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 31206626, 33471991, 34282249). Nine clinical diagnostic laboratories have submitted clinical-significance assessments (all uncertain significance) for this variant to ClinVar after 2014 without evidence for independent evaluation. To our knowledge 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 likely benign.
Sema4, Sema4 RCV000115984 SCV002537025 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-21 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001420894 SCV002761100 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000231285 SCV004020172 uncertain significance Familial cancer of breast 2023-03-09 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV000231285 SCV004217531 uncertain significance Familial cancer of breast 2023-09-29 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004529940 SCV004729311 uncertain significance CHEK2-related disorder 2024-01-05 criteria provided, single submitter clinical testing The CHEK2 c.1133C>T variant is predicted to result in the amino acid substitution p.Thr378Ile. This variant was reported in an individual with breast cancer in the presence of a pathogenic variant in a different gene (Helgadottir et al. 2021. PubMed ID: 34282249). However, this variant has also been documented in controls (Table S3, Weitzel et al. 2019. PMID: 31206626). An in vivo, yeast-based growth rate assay showed this variant behaved similar to wild type CHEK2 (Delimitsou et al. 2019. PMID: 30851065). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128046/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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