Submissions for variant NM_007194.4(CHEK2):c.444+1del

dbSNP: rs1064793780

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484271	SCV000567017	pathogenic	not provided	2015-06-25	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted CHEK2 c.444+1delG or IVS3+1delG and consists of a deletion of a nucleotide at the +1 position in intron 3 of the ATM gene. The normal sequence with the base that is deleted in braces is CAGG[g]tagg, where the capital letters are exonic and the lowercase are intronic. The 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.444+1delG to be a pathogenic variant..
Invitae	RCV001064455	SCV001229359	pathogenic	Familial cancer of breast	2022-12-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419303). This variant is also known as c.444+1delG. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400).
Color Diagnostics, LLC DBA Color Health	RCV001188327	SCV001355358	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	This variant deletes the +1 nucleotide in the intron 3 splice donor site of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, different canonical splice site variants at the +1 position of this splice donor site have been reported in individuals affected with non-Hodgkin lymphoma and breast, pancreatic and prostate cancer (PMID: 15087378, 18058223, 24713400, 26506619, 27488870), and c.444+1G>T is found to disrupt mRNA splicing in RNA derived from carrier cells (PMID: 26506619). 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.
Ambry Genetics	RCV001188327	SCV002632591	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The c.444+1delG variant results from a deletion of one nucleotide at position 444 and involves the canonical splice donor site after coding exon 2 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV001064455	SCV004044457	likely pathogenic	Familial cancer of breast	2023-06-23	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.
Baylor Genetics	RCV001064455	SCV004217713	pathogenic	Familial cancer of breast	2023-01-04	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000484271	SCV001800778	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484271	SCV001970456	pathogenic	not provided		no assertion criteria provided	clinical testing