Submissions for variant NM_007194.4(CHEK2):c.593-11_593-7del

dbSNP: rs863224414

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198112	SCV000253488	likely benign	Familial cancer of breast	2025-01-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000198112	SCV000489651	likely benign	Familial cancer of breast	2016-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000585035	SCV000567733	likely benign	not provided	2020-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579399	SCV000684666	likely benign	Hereditary cancer-predisposing syndrome	2017-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585035	SCV000693078	likely benign	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485140	SCV001467809	uncertain significance	not specified	2020-12-03	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.593-11_593-7delTTCTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 206084 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.593-11_593-7delTTCTT in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000579399	SCV002537623	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000198112	SCV004020092	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000485140	SCV004243024	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585035	SCV005625255	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	The CHEK2 c.593-11_593-7del variant has been reported in the published literature in an individual affected with colorectal cancer who also carried a deleterious variant in the MSH6 gene (PMID: 37088804 (2023)). An experimental study observed that this variant mostly (62%) produced transcripts that lacked exon 5, albeit exon 5 skipping was observed to occur less in the wild-type (4%) (PMID: 37725924 (2024)). Another study also observed exon 5 skipping in varying proportions in reportedly healthy individuals (PMID: 32133419 (2020)). The frequency of this variant in the general population, 0.000035 (3/86422 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute of Human Genetics, University of Leipzig Medical Center	RCV005246777	SCV005900129	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PP3