ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1111C>T (p.His371Tyr) (rs531398630)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677873 SCV000804034 uncertain significance Neoplasm of the breast 2017-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115982 SCV000184610 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000115982 SCV000902667 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764377 SCV000895412 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656834 SCV000149891 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1111C>T at the cDNA level, p.His371Tyr (H371Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). CHEK2 His371Tyr has been reported as a likely pathogenic variant in association with familial breast cancer in individuals of Chinese ancestry, and was identified in 4.2% (5/118) of familial breast cancer cases, 1.8% (16/909) of unselected breast cancer cases, and 0.7% of (9/1228) controls (Liu 2011, Liu 2015). However, Liu et al. (2015) noted the presence of this variant in two individuals also found to harbor a pathogenic BRCA2 variant. Additional smaller studies in Asian populations have identified this variant in breast cancer cases as well as controls (Chen 2008, LeCalvez-Kelm 2011, Baloch 2014). In vitro functional studies have shown that CHEK2 His371Tyr exhibits decreased phosphorylation and CHEK2 kinase activity compared to wild type, but not to the same degree as the negative control, a known kinase-defective pathogenic variant (Liu 2011). 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). CHEK2 His371Tyr is located in the kinase domain (Cai 2009, Roeb 2012). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 His371Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212449 SCV000919213 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1111C>T (p.His371Tyr) variant involves the alteration of a conserved nucleotide that lies within the protein kinase domain (Liu_2011). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 129/280022 control chromosomes, predominantly observed in the East Asian and South Asian subpopulations at a frequency of 0.00424 and 0.001072, respectively, including one homozygote. The frequency in East Asian subpopulation is about 14 times the estimated maximal expected allele frequency of a breast cancer causing pathogenic CHEK2 variant (0.0000284), suggesting this is likely a polymorphism found primarily in the populations of Asian origin. The variant has been reported in numerous publications in both breast cancer patients and healthy controls. One group performed a case-control study in Chinese population that suggested the variant is significantly more frequent in familial breast cancer patients who were negative for mutations in BRCA1/2 than controls (OR = 5.99 [95% CI = 1.98-18.19]; p = 0.002) as well as unselected breast cancer patients (OR = 2.43 [95% CI = 1.07-5.52]; p = 0.034) and suggest the variant confers a moderate risk for breast cancer (Liu_2011). The same study reported incomplete segregation within families and performed functional studies that showed reduced phosphorylation and kinase activity. The variant has also been reported to co-occur with a pathogenic BRCA2 mutation in at least two breast cancer patients (Liu_2015), excluding the variant as the primary cause of disease in the patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance (3) as well as likely pathogenic (1). Taken together, this variant is classified as VUS until additional information becomes available.
Invitae RCV000197709 SCV000254919 uncertain significance Familial cancer of breast 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 371 of the CHEK2 protein (p.His371Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs531398630, ExAC 0.4%). This variant has been reported in individuals affected with breast cancer, diffuse large B-cell lymphoma and pancreatic cancer, as well as unaffected control subjects (PMID: 21244692, 18484200, 16883537, 21618645, 24390236, 23960188, 29667044, 29338689). It has also been reported to arise de novo in an individual affected with a Li–Fraumeni syndrome-like (LFS-L) condition (PMID: 27442652). ClinVar contains an entry for this variant (Variation ID: 128044). Although one study has reported that the c.1111C>T variant confers a significantly increased risk of breast cancer in a Chinese population (familial OR=5.99, 95% CI=1.98-18.19, p=0.002 and unselected: OR=2.43, 95% CI=1.07-5.52, p=0.034) (PMID: 21618645), the clinical significance of this association cannot be established without further studies. Experimental studies have shown that this missense change causes a decrease in phosphorylation and enzymatic activity as compared to wild-type CHEK2 protein. However, the decrease in activity caused by this variant is not as pronounced as the effect caused by a known kinase-disruptive variant (PMID: 21618645). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212449 SCV000601143 uncertain significance not specified 2017-06-30 criteria provided, single submitter clinical testing

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