Submissions for variant NM_007194.4(CHEK2):c.683+1G>C

dbSNP: rs786203650

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255210	SCV000322527	likely pathogenic	not provided	2016-02-08	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.683+1G>C or IVS5+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 5 of the CHEK2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider CHEK2 c.683+1G>C to be a likely pathogenic variant.
Invitae	RCV000529813	SCV000633207	likely pathogenic	Familial cancer of breast	2023-04-27	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 265545). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 32885271). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV000529813	SCV004044032	likely pathogenic	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Color Diagnostics, LLC DBA Color Health	RCV003584585	SCV004361386	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +1 position of intron 5 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.