Submissions for variant NM_007194.4(CHEK2):c.252A>G (p.Glu84=)

gnomAD frequency: 0.04009  dbSNP: rs1805129

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130990	SCV000185912	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV000248875	SCV000311766	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391347	SCV000437727	benign	CHEK2-Related Cancer Susceptibility	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000412125	SCV000488306	benign	Familial cancer of breast	2016-02-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130990	SCV000537350	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV000412125	SCV000560999	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001573826	SCV000883610	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001573826	SCV001882055	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225438	SCV002505170	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000248875	SCV002761117	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000412125	SCV004017048	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412125	SCV004020191	benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
True Health Diagnostics	RCV000130990	SCV000788003	benign	Hereditary cancer-predisposing syndrome	2018-02-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356135	SCV001551209	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Glu84Glu variant was identified in 80 of 2744 proband chromosomes (frequency: 0.03) from families with high risk of HBOC and/or Li-Fraumeni-like syndromes and was present in 43 of 1644 control chromosomes (frequency: 0.03) from healthy individuals (Ingvarsson 2002, Mohamad 2015, Novak 2008, Rashid 2013, Ruijs 2009, Sodha 2002, Staalesen 2004, Kilpivaara 2004, Bayasal 2004). In one study the variant co-occurred with a BRCA2 pathogenic variant (Ingvarsson 2002). The variant was also identified in dbSNP (ID: rs1805129) as “With Likely benign” allele, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Counsyl, Color Genomics and Invitae; and likely benign by Illumina), Clinvitae (3x benign and 2x likely benign), Zhejiang Colon Cancer Database (7x) and was not identified in Cosmic database. The variant was identified in control databases in 9839 (265 homozygous) of 276942 chromosomes at a frequency of 0.04 (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: East Asian in 1688 of 18848 chromosomes (freq: 0.09), Ashkenazi Jewish* in 864 of 10150 chromosomes (freq: 0.085), African in 1565 of 23956 chromosomes (freq: 0.065), South Asian in 1209 of 30778 chromosomes (freq: 0.039), Other in 201 of 6450 chromosomes (freq: 0.031), European (Finnish) in 733 of 25778 chromosomes (freq: 0.028), European (Non-Finnish) in 3152 of 126566 chromosomes (freq: 0.025), Latino in 427 of 34416 chromosomes (freq: 0.012) increasing the likelihood this could be a low frequency benign variant. The p.Glu84Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573826	SCV001800236	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000248875	SCV001808563	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000248875	SCV001906242	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000248875	SCV001956018	benign	not specified		no assertion criteria provided	clinical testing