ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.134C>T (p.Thr45Met)

gnomAD frequency: 0.00008  dbSNP: rs558321010
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214565 SCV000274148 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-22 criteria provided, single submitter clinical testing The p.T45M variant (also known as c.134C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 134. The threonine at codon 45 is replaced by methionine, an amino acid with similar properties. In one study, this variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In another study, this alteration was detected in 1/6385 invasive epithelial ovarian cancer cases and 0/6115 controls of broad European ancestry (Song H et al. J Med Genet, 2021 May;58:305-313). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration has also been identified in a pediatric patient with hypodiploid acute lymphoblastic leukemia (Zhang J et al. N Engl J Med 2015 Dec;373(24):2336-2346). 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 RCV000230142 SCV000289662 uncertain significance Familial cancer of breast 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 45 of the CHEK2 protein (p.Thr45Met). This variant is present in population databases (rs558321010, gnomAD 0.01%). This missense change has been observed in individual(s) with pediatric acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 230559). 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. 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.
GeneDx RCV000523789 SCV000618417 uncertain significance not provided 2023-06-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history including acute lymphocytic leukemia, breast, ovarian, colorectal, and/or other cancers (Zhang et al., 2015; Ballinger et al., 2016; DeRycke et al., 2017; Matejcic et al., 2020; Dorling et al., 2021; Song et al., 2021); This variant is associated with the following publications: (PMID: 24448499, 27498913, 26580448, 28944238, 11733767, 22114986, 32832836, 32546565, 33471991)
Color Diagnostics, LLC DBA Color Health RCV000214565 SCV000903493 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 45 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with sarcoma (PMID: 27498913), colorectal cancer (PMID 28944238) and unspecified pediatric cancer (PMID: 26580448). This variant has been identified in 8/282548 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781305 SCV000919225 uncertain significance not specified 2018-08-31 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.134C>T (p.Thr45Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276880 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134C>T has been reported in the literature in an individual diagnosed with Hypodiploid ALL. This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4 RCV000214565 SCV002537051 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-21 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002485419 SCV002779653 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer 2022-05-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000230142 SCV004215855 uncertain significance Familial cancer of breast 2023-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000523789 SCV004221724 uncertain significance not provided 2023-01-18 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00012 (3/24932 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 28944238 (2017)) and acute lymphoblastic leukemia (PMID: 26580448 (2015)). In a large scale breast cancer association study, the variant was observed in breast cancer cases as well as in control subjects (see LOVD (http://databases.lovd.nl/shared/genes/CHEK2) and PMID: 33471991 (2021)). 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000781305 SCV004242564 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing

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