Submissions for variant NM_007194.4(CHEK2):c.1407G>A (p.Val469=)

gnomAD frequency: 0.00190  dbSNP: rs17881378

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212461	SCV000167692	benign	not specified	2014-01-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000124265	SCV000213083	likely benign	Hereditary cancer-predisposing syndrome	2014-06-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000200578	SCV000252811	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000200578	SCV000488583	likely benign	Familial cancer of breast	2016-05-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124265	SCV000684589	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589618	SCV000698774	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589618	SCV000888104	benign	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212461	SCV002070842	benign	not specified	2021-12-13	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225406	SCV002505154	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124265	SCV002537370	benign	Hereditary cancer-predisposing syndrome	2020-12-12	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149857	SCV003838781	likely benign	Breast and/or ovarian cancer	2021-10-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000200578	SCV004017381	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200578	SCV004020182	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589618	SCV004563300	benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212461	SCV005089751	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589618	SCV001552585	likely benign	not provided		no assertion criteria provided	clinical testing	The CHEK2 p.Val469= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs17881378) as “With other allele” and ClinVar (classified as likely benign by Ambry Genetics, Counsyl, Quest Diagnostics, and Color; and as benign by GeneDx, Invitae, and Integrated Genetics). The variant was identified in control databases in 152 of 260148 chromosomes at a frequency of 0.0006, 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 143 of 22576 chromosomes (freq: 0.006334), Latino in 7 of 34216 chromosomes (freq: 0.000205), and European (Non-Finnish) in 2 of 122014 chromosomes (freq: 0.000016), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Val469= 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.