ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115982 SCV000184610 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-30 criteria provided, single submitter clinical testing The p.H371Y variant (also known as c.1111C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1111. The histidine at codon 371 is replaced by tyrosine, an amino acid with similar properties. In one study, this alteration was detected at a significantly increased frequency in both unselected and familial Chinese breast cancer patients compared to ethnically-matched controls (unselected: OR=2.43, p=0.034, 95% CI=1.07-5.52; familial OR=5.99, p=0.002, 95% CI=1.98-18.19). This group performed functional studies and indicated that CHEK2 p.H371Y showed impaired phosphorylation and DNA damage response, however, there is no quantitation of the assays, and phosphorylation impairment is not clearly demonstrated in the data presented (Liu Y et al. Hum. Mutat. 2011 Sep;32:1000-3). Three additional case control studies found the p.H371Y variant was detected in 1/70 breast cancer patients and not in 70 ethnically matched healthy controls in one cohort; in 1/74 Chinese familial breast cancer patients and not in 50 Chinese healthy controls from another cohort; and in 2/1313 breast cancer patients and in 1/1123 ethnically matched healthy controls from another cohort (Baloch AH et al. Mol. Biol. Rep. 2014 Feb;41:1103-7; Chen W et al. Adv Ther. 2008 May; 25:496-501; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). Further, this alteration was identified in 3/120 Korean BRCA1/2 negative hereditary breast cancer patients (Park JS et al. BMC Cancer. 2018 01;18:83). However, a study of 117 South Korean patients with epithelial ovarian cancer reports two apparently unrelated patients with CHEK2 c.1111C>T in co-occurrence with a pathogenic CHEK2 mutation, p.R519*, although phase was not reported (Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925). In addition, this variant was detected in conjunction with a pathogenic PMS2 mutation in a Japanese patient diagnosed with colorectal cancer at 58y and pancreatic cancer at 59y (Ohmoto A et al. J Gastroenterol. 2018 Oct;53:1159-1167). This alteration is not enriched in Ambry internal Asian breast cancer population compared to population databases (Ambry Internal Data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197709 SCV000254919 uncertain significance Familial cancer of breast 2020-10-27 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. This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein function (PMID: 21618645, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656834 SCV000601143 uncertain significance not provided 2020-08-28 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677873 SCV000804034 uncertain significance Breast neoplasm 2017-08-31 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
Color Health, Inc RCV000115982 SCV000902667 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing This missense variant replaces histidine with tyrosine at codon 371 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). A functional study has shown that this variant causes a partial reduction in CHEK2 kinase activity (PMID: 21618645), while a different study has shown normal CHEK2 function in complementation assay in yeast (PMID: 30851065). A case-control study with a Chinese female population has reported a significant association with breast cancer (5/118 familial breast cancer, OR=5.99, 95% CI=1.98-18.19; 16/909 unselected breast cancer: OR=2.43, 95% CI=1.07-5.52; 9/1228 controls) (PMID: 21618645). However, two other breast cancer case-control studies in a large Japanese cohort (7051 cases and 11241 controls) and in a large Caucasian female cohort (1303 cases and 1109 controls) reported this variant in both affected and unaffected individuals and did not observed significant association with disease (PMID: 21244692, 30287823). This variant is fairly common in the general population and has been identified in 127/280624 chromosomes (84/19952 East Asian chromosomes and 34/30616 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting reports of breast cancer association and inconsistent functional study results, 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 RCV000212449 SCV000919213 uncertain significance not specified 2021-06-05 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1111C>T (p.His371Tyr) results in a conservative amino acid change located in the Protein kinase domain (IPR099710) 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 0.00051 in 254090 control chromosomes, predominantly at a frequency of 0.0041 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1111C>T has been reported in the literature in individuals affected with Breast Cancer, in settings of multigene cancer panel testing, in unaffected controls (example, Baloch_2013, LeCalvez-Kelm_2011, Leedom_2016, Young_2016, Liu_2011, Momozawa_2018) and in settings of other cancers such as diffuse large B cell lymphomas (example, deMiranda_2013) and a case report of a reportedly de-novo occurrence in a Chinese family with Li-Fraunemi like syndrome (Zhuang_2016). The case report of the de-novo occurrence is questionable as the parents of the proband were not tested for the variant and the de-novo status was interpreted based on the genotypes of her two healthy sisters. Furthermore, the high frequency of this variant among East Asian cohorts casts additional doubt on the strength of this evidence. 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 an unspecified pathogenic BRCA2 mutation in at least two breast cancer patients (Liu_2015), excluding the variant as the primary cause of disease in the patients. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or any CHEK2-related tumors. At least one additional recent publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a yeast based experimental system evaluating the ability to resume cell growth and proliferation by repair of methyl-methanesulfonate (MMS) induced DNA damage (Delimitsou_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as a VUS-possibly benign until additional peer derived clinical and functional consensus in the field is established.
Mendelics RCV000197709 SCV001141355 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030625 SCV001193559 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656834 SCV001245711 uncertain significance not provided 2020-10-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355387 SCV001550261 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.His371Tyr variant was identified in 57 of 8408 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer, diffuse large B cell lymphomas, or hematologic cancer and was identified in 3 of 2658 control chromosomes (frequency: 0.001) from healthy individuals (Baloch 2014, de Miranda 2013, Eoh 2017, Liu 2015, Le Calvez-Kelm 2011, Rashid 2013). The variant was also identified in dbSNP (ID: rs531398630) as ‚ With Likely pathogenic allele‚Äù, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano), Cosmic, MutDB, and the Zhejiang University Database. The variant was identified in control databases in 119 of 275180 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: ‚ Other‚Äù in 1 of 6440 chromosomes (freq: 0.0002), Latino in 1 of 34404 chromosomes (freq: 0.00003), European in 4 of 125344 chromosomes (freq: 0.00003), East Asian in 80 of 18868 chromosomes (freq: 0.004), and South Asian in 33 of 30782 chromosomes (freq: 0.001); it was not observed in the African, Ashkenazi Jewish, or Finnish populations. The p.His371 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the p.His371Tyr amino acid change is within the activation loop of the CHEK2 kinase domain, which is essential for activation of CHEK2 in response to DNA damage (Baloch 2014). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
University Health Network,Princess Margaret Cancer Centre RCV001527478 SCV001738496 uncertain significance Familial cancer of breast; Neoplasm of ovary; Lung cancer 2021-03-19 no assertion criteria provided clinical testing

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