ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: rs531398630
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656834 SCV000149891 uncertain significance not provided 2022-09-29 criteria provided, single submitter clinical testing Reported in individuals with breast cancer, but also in unaffected controls (Chen et al., 2008; LeCalvez-Kelm et al., 2011; Baloch et al., 2014; Caminsky et al., 2016; Momozawa et al., 2018; Pfaendler and Randall, 2019; Chen et al., 2020; Lang et al., 2020); Published functional studies are inconclusive/conflicting: decreased phosphorylation and CHEK2 kinase activity in one study, but DNA damage response, cell growth rates, and Kap1 phosphorylation similar to wild-type in other studies (Liu et al., 2011; Delimitsou et al., 2019; Boonen et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1240C>T; p.His414Tyr; This variant is associated with the following publications: (PMID: 23806170, 16883537, 21618645, 28580595, 31220302, 31296309, 30826992, 31358837, 32801835, 24390236, 25629968, 18484200, 21244692, 27442652, 23960188, 26787654, 26898890, 28152038, 27751358, 28873162, 28961279, 29020732, 23318652, 29338689, 29879026, 29506128, 28301460, 29667044, 29470806, 28553140, 27783279, 27621404, 30723762, 29356917, 30851065, 30630526, 30287823, 31054147, 31472684, 32091409, 33313162, 31742824, 33322746, 30975222, 31980526, 32521533, 34426522, 32906215, 34903604, 31721094, 35643632, 28888541, 34926254, 22419737, 19782031, 25884806, 34282142, 32923877, 34716641, 34630562, 34567566)
Ambry Genetics RCV000115982 SCV000184610 likely benign Hereditary cancer-predisposing syndrome 2021-06-15 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000197709 SCV000254919 uncertain significance Familial cancer of breast 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 371 of the CHEK2 protein (p.His371Tyr). This variant is present in population databases (rs531398630, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, diffuse large B-cell lymphoma, gastric cancer and pancreatic cancer, as well as unaffected control subjects (PMID: 16883537, 18484200, 21244692, 21618645, 23960188, 24390236, 27442652, 29338689, 29667044, 32091409, 32521533). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128044). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 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 benign not provided 2022-10-21 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 RCV002477284 SCV000895412 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer 2022-02-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115982 SCV000902667 likely benign Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter clinical testing
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 ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000656834 SCV001245711 likely benign not provided 2023-09-01 criteria provided, single submitter clinical testing CHEK2: BP4, BS1
Genetic Services Laboratory, University of Chicago RCV000212449 SCV002070847 uncertain significance not specified 2019-03-04 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000197709 SCV002556663 uncertain significance Familial cancer of breast 2021-07-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004529939 SCV004114856 uncertain significance CHEK2-related disorder 2023-03-27 criteria provided, single submitter clinical testing The CHEK2 c.1111C>T variant is predicted to result in the amino acid substitution p.His371Tyr. This variant has been reported in individuals with multiple types of cancers including: breast (Liu et al. 2011. PubMed ID: 21618645; Baloch et al. 2014. PubMed ID: 24390236; Sung et al. 2017. PubMed ID: 28961279; Chen et al. 2020. PubMed ID: 32091409; Table A2 - Greville-Heygate et al. 2020. PubMed ID: 32923877), ovarian (Table S2 - Li et al. 2019. PubMed ID: 31472684), pancreatic (Lowery et al. 2018. PubMed ID: 29506128; Ohmoto et al. 2018. PubMed ID: 29667044), diffuse large B-cell lymphoma (de Miranda et al. 2013. PubMed ID: 23960188), uterine broad ligament ependymoma (Yin et al. 2021. PubMed ID: 34716641), and an individual with Li–Fraumeni syndrome (Zhuang et al. 2016. PubMed ID: 27442652). Functional studies provide conflicting evidence of this variants impact on function (Liu et al. 2011. PubMed ID: 21618645; Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.42% of alleles in individuals of East Asian descent in gnomAD including in the homozygous state in one individual (http://gnomad.broadinstitute.org/variant/22-29091846-G-A). In ClinVar this variant has conflicting interpretations including benign, likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Neuberg Centre For Genomic Medicine, NCGM RCV003448266 SCV004176642 uncertain significance Bone osteosarcoma 2023-02-14 criteria provided, single submitter clinical testing The missense c.1111C>T(p.His371Tyr) variant in CHEK2 gene has been reported in heterozygous state in individuals with susceptibility to breast cancer (Liu Y, et. al., 2015). The p.His371Tyr variant is reported with an allele frequency of 0.05% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Benign/Likely benign/ Uncertain Significance (multiple submission). The amino acid change p.His371Tyr in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 371 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Varint of Uncertain Significance (VUS).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212449 SCV004243017 uncertain significance not specified 2024-02-06 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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