ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1270T>C (p.Tyr424His) (rs139366548)

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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 RCV000115993 SCV000186576 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000115993 SCV000537514 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Counsyl RCV000197909 SCV000785377 uncertain significance Familial cancer of breast 2017-07-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515214 SCV000611450 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000590008 SCV000149902 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1270T>C at the cDNA level, p.Tyr424His (Y424H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). Although one functional study revealed loss of activity with respect to CHEK2-mediated response to DNA damage, the variant performed comparably to wild type in a different yeast complementation assay (Tischkowitz 2008, Roeb 2012). While this variant has been observed in individuals with a personal and/or family history of breast/ovarian cancer (Laitman 2007, Couch 2015), it has demonstrated incomplete segregation with disease in breast and prostate cancer families, and a case-control study found no significant difference in the frequency of this variant among Ashkenazi Jewish breast or prostate cancer patients and controls (Tischkowitz 2008, Roeb 2012). 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). This variant 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 currently available evidence, it is unclear whether CHEK2 Tyr424His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590008 SCV000698768 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1270T>C (p.Tyr424His) variant located in the protein kinase domain (via Roeb_2012) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed controls with an allele frequency of 39/118030 control chromosomes at a frequency of 0.0003304, which is approximately 12 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals and indicate that the variant does not segregate with disease in multiple families (Roeb_2012 and Tischkowitz_2015). Although, yeast studies provide conflicting evidence as to whether the variant has a deleterious or benign effect. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae RCV000197909 SCV000254922 uncertain significance Familial cancer of breast 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 424 of the CHEK2 protein (p.Tyr424His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs139366548, ExAC 0.05%). This variant was reported in families affected with breast, uterine, and prostate cancer (PMID: 18085035, 18571837, 22419737). Currently, there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22419737, 18571837). This variant was reported in unaffected individuals at a similar frequency to individuals with prostate cancer (PMID: 18571837). ClinVar contains an entry for this variant (Variation ID: 128054). Experimental studies have reported conflicting evidence regarding the impact of this variant on CHEK2 function in a yeast-based assay (PMID: 22419737, 18571837). Additionally, 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: "Probably 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.
Mendelics RCV000197909 SCV000839462 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000590008 SCV000806865 likely benign not provided 2017-10-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212458 SCV000601147 uncertain significance not specified 2016-09-02 criteria provided, single submitter clinical testing

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