Submissions for variant NM_007194.4(CHEK2):c.1260-10C>G

gnomAD frequency: 0.00006  dbSNP: rs730881706

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160459	SCV000211024	benign	not specified	2014-08-13	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.
Invitae	RCV000199374	SCV000253480	likely benign	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581114	SCV000684577	benign	Hereditary cancer-predisposing syndrome	2017-03-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160459	SCV000917228	benign	not specified	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.1260-10C>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 6/110696 control chromosomes (1 homozygote) in ExAC and 17/275124 control chromosomes in gnomAD (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at frequency of 0.0001 (6/59812 in ExAC) and 0.0001355 (17/125452 in genomAD). These frequency are about 4 ~ 5 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 European (Non-Finnish) origin. This variant has been reported in one BrC patient without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000160459	SCV002066144	likely benign	not specified	2020-09-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000581114	SCV002537037	likely benign	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149974	SCV003838123	likely benign	Breast and/or ovarian cancer	2022-05-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001528944	SCV004221722	uncertain significance	not provided	2023-01-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00026 (13/50354 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on CHEK2 mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528944	SCV001741561	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001528944	SCV001905856	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528944	SCV001956741	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528944	SCV001980650	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001528944	SCV002036506	likely benign	not provided		no assertion criteria provided	clinical testing