Submissions for variant NM_007194.4(CHEK2):c.538C>T (p.Arg180Cys)

gnomAD frequency: 0.00051  dbSNP: rs77130927

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588124	SCV000149933	likely benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Case-control studies are inconclusive regarding association with breast cancer (Southy 2016, Decker 2017); Observed in individuals with breast, prostate, or ovarian cancer (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017); Also known as CHEK2 c.667C>T (p.Arg223Cys); Published functional studies are inconclusive: intermediate response to DNA damage (Walsh 2011, Roeb 2012); This variant is associated with the following publications: (PMID: 26757417, 26483394, 28580595, 18085035, 30826992, 31060593, 25629968, 12533788, 22995991, 25980754, 25525159, 15095295, 20643596, 21618645, 24549055, 21244692, 27153395, 27498913, 22419737, 27595995, 21744992, 18058223, 18996005, 27621404, 23960188, 27783279, 22006311, 23555315, 28188963, 28452373, 28779002, 19782031, 29879026, 29470806, 30287823, 30851065, 31050813, 31422574, 29667044, 29263802, 32566746, 32041497, 33326660, 32906215)
Ambry Genetics	RCV000116024	SCV000185905	benign	Hereditary cancer-predisposing syndrome	2016-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196561	SCV000253487	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490304	SCV000267255	uncertain significance	Malignant tumor of prostate	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000196561	SCV000488845	uncertain significance	Familial cancer of breast	2016-07-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212426	SCV000594118	uncertain significance	not specified	2016-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116024	SCV000689694	benign	Hereditary cancer-predisposing syndrome	2016-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588124	SCV000698810	likely benign	not provided	2016-08-08	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116024	SCV000747819	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000196561	SCV000839487	benign	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588124	SCV000889337	likely benign	not provided	2023-07-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588124	SCV001153648	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030689	SCV001193565	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV004556732	SCV001310488	uncertain significance	CHEK2-related cancer predisposition	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000196561	SCV001368127	uncertain significance	Familial cancer of breast	2019-07-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6.
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001030689	SCV001438608	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588124	SCV001471442	likely benign	not provided	2022-01-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588124	SCV002009490	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798358	SCV002043408	uncertain significance	Breast and/or ovarian cancer	2022-09-14	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001030689	SCV002505166	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116024	SCV002537611	likely benign	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000196561	SCV002556371	uncertain significance	Familial cancer of breast	2020-10-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212426	SCV002761109	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196561	SCV004020199	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000588124	SCV004225583	uncertain significance	not provided	2022-03-21	criteria provided, single submitter	clinical testing	BS3_supporting
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588124	SCV001549905	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CHEK2 p.Arg180Cys variant was identified in 172 of 93852 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer, prostate cancer and Lynch syndrome and was present in 147 of 89446 control chromosomes (frequency: 0.002) from healthy individuals (Dong 2003, Dufault 2004, Kleibl 2008, Laitman 2007, Mohamad 2015, Mohelnikova Duchonova 2010, Ng 2016, Southey 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs77130927) as “With other allele”, ClinVar (classified as benign by Color Genomics, Ambry Genetics, and Mendelics Analise Genomica; as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Counsyl, and 4 other submitters). The variant was identified in control databases in 261 of 277166 chromosomes at a frequency of 0.0009, 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 14 of 24018 chromosomes (freq: 0.0006), Other in 6 of 6468 chromosomes (freq: 0.0009), Latino in 2 of 34420 chromosomes (freq: 0.00006), European (Non-Finnish) in 153 of 126674 chromosomes (freq: 0.001), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), East Asian in 58 of 18866 chromosomes (freq: 0.003), European (Finnish) in 5 of 25788 chromosomes (freq: 0.0002), and South Asian in 21 of 30780 chromosomes (freq: 0.0007). In a functional yeast assay, the response of the p.Arg180Cys CHEK2 variant to DNA damage was found to be decreased to 0.64 of wild type (1.00; Roeb 2012). A large study of the Breast Cancer Association Consortium found an association with breast cancer risk to be 1.33 odds ratio (Southey 2016). The p.Arg180 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.
PreventionGenetics, part of Exact Sciences	RCV004529943	SCV004708760	likely benign	CHEK2-related disorder	2023-03-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).