ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129670 SCV000184468 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.R181H variant (also known as c.542G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 542. The arginine at codon 181 is replaced by histidine, an amino acid with highly similar properties. Germline alterations at this amino acid position have been reported in individuals from cohorts of various cancer patients including prostate cancer, neuroblastoma, breast cancer, and Hodgkin's lymphoma, but not in controls (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Dufault MR et al. Int. J. Cancer. 2004 Jun;110:320-5; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Heymann S et al. Radiat Oncol. 2010 Nov;5:104; Havranek O et al. Neoplasma. 2011;58:392-5; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Pugh TJ et al. Nat. Genet. 2013 Mar;45:279-84). 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 limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000114761 SCV000210965 likely benign not provided 2021-02-10 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 29700634, 31118792, 21744992, 15095295, 12533788, 23334666, 26506619, 28055978, 27720647, 28418444, 16982735, 22419737, 30067863, 21059199, 16835864, 29752822, 28580595, 30851065, 31050813, 30287823, 29520813, 31056747, 32906215)
Invitae RCV000233960 SCV000289689 uncertain significance Familial cancer of breast 2020-10-11 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 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 Health, Inc RCV000129670 SCV000684656 likely benign Hereditary cancer-predisposing syndrome 2021-02-17 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; Bone 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 2020-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Baylor Genetics RCV001294022 SCV001482782 uncertain significance Li-Fraumeni syndrome 2 2019-05-28 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357854 SCV001553443 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Arg181His variant was identified in 4 of 3908 proband chromosomes (frequency: 0.001) from individuals with non-hodgkins lymphoma, neuroblastoma, breast and prostate cancer and was not identified in 2736 control chromosomes from healthy individuals (Dong 2003,Pugh 2013, Dufault 2004, Havranek 2015). The variant was identified in dbSNP (rs121908701) as “with pathogenic allele”, in ClinVar (interpreted as "uncertain significance" by Invitae, Color and 6 others, "pathogenic" by OMIM and not provided 1 other). The variant was identified in control databases in 34 of 277,176 chromosomes (1 homozygous) at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,026 chromosomes (freq: 0.00004), Latino in 1 of 34,420 chromosomes (freq: 0.00003), European in 3 of 126,676 chromosomes (freq: 0.00002), East Asian in 25 of 18,864 chromosomes (freq: 0.001), and South Asian in 4 of 30,782 chromosomes (freq: 0.0001). The variant was not observed in the Other, Ashkenazi Jewish and Finnish, populations. The variant is located within the Forkhead Associate Domain, but further studies are required to determine if it affects protein function. The p.Arg181His 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.