ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115993 SCV000186576 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-22 criteria provided, single submitter clinical testing Insufficient evidence;Conflicting evidence
Invitae RCV000197909 SCV000254922 uncertain significance Familial cancer of breast 2020-01-10 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, 30851065). 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.
Color RCV000115993 SCV000537514 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590008 SCV000601147 uncertain significance not provided 2019-08-19 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
Integrated Genetics/Laboratory Corporation of America RCV001175351 SCV000698768 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1270T>C (p.Tyr424His) results in a 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 0.00029 in 250548 control chromosomes (gnomAD). The observed variant frequency is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Li-Fraumeni Syndrome phenotype (2.8e-05), strongly suggesting that the variant is benign. However, this observation needs to be cautiously considered since the majority of occurrences was detected in the Ashkenazi Jewish subpopulation (a confined population) and additionally, the variant is located in a region of the gene indicated to be affected by pseudogene interference. c.1270T>C has been reported in the literature in individuals affected with cancer, including breast, prostate and colon cancer (e.g. Couch_2015, Kleiblova_2019, Laitman_2007, Roeb_2012, Tischkowitz_2008, Tung_2015). Family studies carried out by some of these studies demonstrated the variant did not segregate with disease (e.g. Roeb_2012, Tischkowitz_2008). Although, functional studies provided conflicting evidence as to whether the variant has a deleterious or benign effect (Delimitsou_2019, Kleiblova_2019, Roeb_2012, Tischkowitz_2008). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=8) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000197909 SCV000785377 uncertain significance Familial cancer of breast 2017-07-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590008 SCV000806865 likely benign not provided 2017-10-10 criteria provided, single submitter clinical testing
Mendelics RCV000197909 SCV000839462 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001147976 SCV001308836 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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