Submissions for variant NM_007194.4(CHEK2):c.541C>T (p.Arg181Cys)

gnomAD frequency: 0.00006  dbSNP: rs137853010

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164479	SCV000215126	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-15	criteria provided, single submitter	clinical testing	The p.R181C variant (also known as c.541C>T), located in coding exon 3 of the CHEK2 gene, results from a C to T substitution at nucleotide position 541. The arginine at codon 181 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals diagnosed with breast cancer, colorectal cancer, and/or prostate cancer (Zheng L et al. Hum. Mutat. 2006 Oct;27:1062-3; Wu Y et al. Prostate. 2018 Jun;78:607-615; Kleibl Z et al. Breast Cancer Res. Treat. 2008 Nov;112:159-64; Hauke J et al. Cancer Med. 2018 Apr;7:1349-1358; Kleibl Z et al. Eur. J. Cancer. 2009 Mar;45:618-24). Functional studies have shown that this alteration results in partially reduced Chk2 kinase activity and, in a yeast-based assay to assess in vivo Chk2-mediated response to cell damage, this alteration showed an intermediate response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196466	SCV000254944	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the CHEK2 protein (p.Arg181Cys). This variant is present in population databases (rs137853010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with CHEK2-related conditions (PMID: 18058223, 18996005, 22419737, 29522266, 36468172). ClinVar contains an entry for this variant (Variation ID: 5597). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16835864, 22419737, 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.
GeneDx	RCV000216866	SCV000278922	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Observed in individuals with CHEK2-related cancers, but also in unaffected controls (PMID: 12533788, 16835864, 16941491, 18058223, 18996005, 28779002, 29522266, 30287823, 29520813, 32923877, 33471991, 34711244, 36243179, 33309985, 32980694); Published functional studies are conflicting: some show reduced response to DNA damage and kinase activity, while others show kinase activity and DNA damage response comparable to wild-type (PMID: 16835864, 22419737, 30851065, 31050813); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.670C>T p.(R224C); This variant is associated with the following publications: (PMID: 26822949, 16835864, 27157322, 12533788, 22419737, 18058223, 16941491, 18996005, 19782031, 21765476, 29520813, 28873162, 30851065, 31050813, 30287823, 34711244, 34426522, 36468172, 28125078, 28779002, 26580448, 29522266, 32923877, 33471991, 32980694, 36243179, 33309985, 32906206, 38630906)
Counsyl	RCV000196466	SCV000489682	uncertain significance	Familial cancer of breast	2016-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164479	SCV000910863	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 181 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). Functional studies have shown conflicting results, showing the mutant protein to be functional (PMID: 16835864, 30851065, 31050813), exhibit partially reduced activity (PMID: 22419737), or no activity (PMID: 36468172). This variant has been reported in individuals affected with breast cancer (PMID: 18058223, 22419737, 29522266, 34711244), colorectal cancer (PMID: 18996005, 34711244), prostate cancer (PMID: 12533788, 16835864, 29520813), and other hereditary cancers (PMID: 26580448, 28873162, 36468172). In a large breast cancer case-control study, this variant has been observed in 6/60466 cases and 3/53461 unaffected controls (OR=1.768, 95%CI 0.442 to 7.071; p-value=0.515; Leiden Open Variation Database DB-ID CHEK2_000021)(PMID: 33471991). This variant has been observed together with pathogenic BRCA1 and BRCA2 variants in individuals affected with breast cancer (Color internal data). This variant has been identified in 31/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000196466	SCV001251963	uncertain significance	Familial cancer of breast	2020-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193084	SCV001361674	uncertain significance	not specified	2022-07-27	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.541C>T (p.Arg181Cys) 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 0.00011 in 251404 control chromosomes, predominantly at a frequency of 0.00052 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant might be a benign polymorphism. c.541C>T has been reported in the literature in individuals affected with prostate-, breast- and colorectal cancer, as well as in pediatric acute lymphoblastic leukemia and Ewing sarcoma, and multiple primary tumors (Dong_2003, Wu_2018, Kleibl_2008, Kleibl_2009, Zhang_2016, Brohl_2017, Dorling_2021, Wallander_2021), however it was also reported in several unaffected controls (Momozawa_2018, Kleiblova_2019, Narang_2020, Dorling_2021, Mizukami_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with the disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated for the variant protein unaffected autophosphorylation, but partially reduced kinase activity in a mammalian cell system (Wu_2006), as well as an intermediate response to DNA damage in a yeast complementation assay (Roeb_2012). However later studies reported the variant to be similar to WT in a yeast complementation assay (Delimitsou_2019) and with unaffected kinase activity in mammalian cells (Kleiblova_2019). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000216866	SCV002009489	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216866	SCV002046832	uncertain significance	not provided	2021-04-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164479	SCV002537613	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000196466	SCV002581406	uncertain significance	Familial cancer of breast	2022-05-13	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000196466	SCV003926628	uncertain significance	Familial cancer of breast	2023-05-29	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the CHEK2 gene (c.541C>T). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the CHEK2 protein (p.Arg181Cys).This amino acid position is poorly conserved(PhyloP=2.3). This variant is present in population databases (rs137853010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast, ovarian and colorectal cancer (PMID: 18058223, 18996005, 22419737, 29522266). ClinVar contains an entry for this variant (Variation ID: 5597). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.
Myriad Genetics, Inc.	RCV000196466	SCV004020202	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193084	SCV004024659	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000196466	SCV004217542	uncertain significance	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000216866	SCV005197504	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000196466	SCV005368091	uncertain significance	Familial cancer of breast	2024-04-23	criteria provided, single submitter	clinical testing	Criteria applied: PM5
OMIM	RCV000005945	SCV000026127	pathogenic	Prostate cancer, somatic	2003-02-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000216866	SCV001959548	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000216866	SCV001971611	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001193084	SCV003839357	uncertain significance	not specified	2022-06-10	no assertion criteria provided	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.541C>T, in exon 4 that results in an amino acid change, p.Arg181Cys. This sequence change has been previously described in one individual with prostate cancer (PMID: 29520813) and has been described in the gnomAD database with a frequency of 0.011% in the overall population (dbSNP rs137853010). The p.Arg181Cys change affects a poorly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg181Cys substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg181Cys change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV004737137	SCV005362769	uncertain significance	CHEK2-related disorder	2024-06-19	no assertion criteria provided	clinical testing	The CHEK2 c.541C>T variant is predicted to result in the amino acid substitution p.Arg181Cys. This variant has been reported in individuals with a history of colorectal, breast, or prostate cancers and was absent from control cohorts (Dong et al. 2003. PubMed ID: 12533788; Wu et al. 2006. PubMed ID: 16835864; Kleibl et al. 2008. PubMed ID: 18058223; Kleibl et al. 2009. PubMed ID: 18996005; Wu et al. 2018. PubMed ID: 29520813). Functional assays have demonstrated that this variant impacts CHEK2 kinase activity and has an intermediate response to DNA damage (Roeb et al. 2012. PubMed ID: 22419737; Wu et al. 2006. PubMed ID: 16835864). Results of an in vivo, yeast‐based, functional assay indicated that this variant did not impact growth, which suggests this allele may be functional (i.e. benign) (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.052% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5597/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.