Submissions for variant NM_007194.4(CHEK2):c.793-11G>A

gnomAD frequency: 0.00054  dbSNP: rs5997387

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581846	SCV000689723	likely benign	Hereditary cancer-predisposing syndrome	2015-04-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000663321	SCV000786591	likely benign	Familial cancer of breast	2018-06-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679679	SCV000806888	likely benign	not provided	2017-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679679	SCV001159435	likely benign	not provided	2020-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000679679	SCV001865675	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000663321	SCV002422145	benign	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000581846	SCV002537639	likely benign	Hereditary cancer-predisposing syndrome	2021-02-08	criteria provided, single submitter	curation
Ambry Genetics	RCV000581846	SCV002676567	likely benign	Hereditary cancer-predisposing syndrome	2015-10-09	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.
Myriad Genetics, Inc.	RCV000663321	SCV004020089	benign	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered 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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679679	SCV001552933	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CHEK2 c.793-11G>A variant was identified in one human breast cancer cell line however the frequency of this variant in an affected population was not provided (Wasielewski 2010). The variant was also identified in dbSNP (ID: rs5997387) as "With Likely benign allele", in ClinVar (classified as likely benign by Counsyl, Color and Prevention Genetics). The variant was identified in control databases in 44 of 274956 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 43 of 23932 chromosomes (freq: 0.002), Latino in 1 of 34138 chromosomes (freq: 0.00003); it was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.793-11G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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.