ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.542G>A (p.Arg181His) (rs121908701)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129670 SCV000184468 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000114761 SCV000210965 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.542G>A at the cDNA level, p.Arg181His (R181H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, also published as CHEK2 Arg224His, has been observed in patients with neuroblastoma, lymphoma, breast cancer, and prostate cancer, and was absent among controls; however, the differences were not statistically significant (Dong 2003, Dufault 2004, Havranek 2011, Pugh 2013, Havranek 2015, Kaur 2018). CHEK2 Arg181His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FHA domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Arg181His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233960 SCV000289689 uncertain significance Familial cancer of breast 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 181 of the CHEK2 protein (p.Arg181His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121908701, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with prostate cancer, neuroblastoma, breast cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma (PMID: 12533788, 23334666, 15095295, 21744992, 26506619). ClinVar contains an entry for this variant (Variation ID: 5598). This variant has been reported not to substantially affect CHEK2 protein function (PMID: 30851065, 31050813). 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.
Counsyl RCV000233960 SCV000488568 uncertain significance Familial cancer of breast 2016-04-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114761 SCV000601173 uncertain significance not provided 2019-02-20 criteria provided, single submitter clinical testing
Color RCV000129670 SCV000684656 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing
Mendelics RCV000233960 SCV000839486 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765623 SCV000896948 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030688 SCV001193564 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV001149529 SCV001310487 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114761 SCV001334551 likely benign not provided 2020-02-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193685 SCV001362697 likely benign not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) 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 0.00014 in 251408 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.542G>A has been reported in the literature in a Japanese case control study of individuals with breast cancer with no reported association (Momozawa_2018), Hodgkins lymphoma, Non-Hodgkins lymphoma, sporadic prostate cancer, Neuroblastoma, and at-least one individual with breast cancer from a family testing negative for mutations in BRCA1 and 2 genes (Havranek_2011, Havranek_2015, Dong_2003, Pugh_2013, Dufault_2004). These reports do not provide unequivocal conclusions about the association of this variant with any of these cancers and some even cite this in the context of a neutral variant (Havranek_2011) or a non-significant association (Dufault_2004). At least two recent publications report experimental evidence evaluating an impact on protein function. Both studies showed no damaging effect of this variant using an in-vivo yeast based assay evaluating the ability to repair MMS (methylmethanesulfonate) induced DNA damage (Delimitsou_2019), and an in-vitro cell-based assay quantifying KAP1-S473 phosphorylation in non transformed human RPE1-CHEK2 knock out cells (Kleibova_2019). Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Some of these submitters list overlapping evidence utilized in the context of this evaluation. Our laboratory has previously classified this variant as a VUS. However, based on the evidence outlined above further supplemented by the reproducible neutral functional impact reported across two independent studies (Delimitsou_2019, andKleibova_2019), the variant was re-classified as likely benign.
OMIM RCV000005946 SCV000026128 pathogenic Prostate cancer, somatic 2003-02-01 no assertion criteria provided literature only
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114761 SCV000148656 not provided not provided no assertion provided not provided

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