Submissions for variant NM_007194.4(CHEK2):c.1096-4T>C

gnomAD frequency: 0.00001  dbSNP: rs587782840

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132429	SCV000187522	likely benign	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000590391	SCV000329283	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
Counsyl	RCV000412166	SCV000488624	uncertain significance	Familial cancer of breast	2016-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590391	SCV000698760	uncertain significance	not provided	2016-03-01	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide located in an intronic position not widely known to affect splicing. Mutation taster predicts disease causing outcome for this substitution while 5/5 in silico tools via Alamut predict the variant not to have an effect on splicing. The variant was found in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.0046% which exceeds the maximal expected allele frequency of a disease causing CHEK2 allele (0.0028%) indicating neutrality. To our knowledge, the variant was not reported in affected individuals and in vitro/vivo studies assessing the impact of the variant on slicing were not published at the time of scoring either. A clinical laboratory classifies variant as Uncertain" (without evidence to independently evaluate). Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available.
Invitae	RCV000412166	SCV000757402	likely benign	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132429	SCV000903060	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412166	SCV004020106	likely benign	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590391	SCV004221715	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000036 (9/248762 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CHEK2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.