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

dbSNP: rs786203650

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167053	SCV000217880	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-24	criteria provided, single submitter	clinical testing	The c.683+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the CHEK2 gene. This alteration has been reported in breast cancer patients (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879) and individuals undergoing multi-gene panel testing for hereditary cancer (Sutcliffe EG et al. Cancer Genet. 2020 Aug;246-247:12-17; Espinel W et al. Cancers (Basel). 2022 May;14(10)). 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204794	SCV000259449	likely pathogenic	Familial cancer of breast	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with personal and/or family history of cancer (PMID: 27751358, 32885271). ClinVar contains an entry for this variant (Variation ID: 187334). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (internal data). 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.
GeneDx	RCV000216702	SCV000279478	likely pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individual(s) with breast cancer and in an individual with Ewing sarcoma (Lerner-Ellis et al., 2021; Gillani et al., 2022); This variant is associated with the following publications: (PMID: 32805687, 21876083, 24713400, 32885271, 27751358, 36497448, 35512711, 35626031)
Counsyl	RCV000204794	SCV000488795	likely pathogenic	Familial cancer of breast	2016-06-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216702	SCV000888119	pathogenic	not provided	2017-11-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167053	SCV000913592	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	This variant causes a G to T 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, functional studies have not been reported for this variant. This variant has been reported in at least four individuals who underwent cancer genetic testing (PMID: 27751358, 32885271). 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.
Myriad Genetics, Inc.	RCV000204794	SCV004020144	likely pathogenic	Familial cancer of breast	2023-03-08	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	RCV000204794	SCV004217668	pathogenic	Familial cancer of breast	2023-06-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358419	SCV001554144	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 c.683+1G>T variant was identified in 3 of 91758 proband chromosomes (frequency: 3.3E-05) from individuals or families submitted to a clinical lab for hereditary cancer panel testing however the specific medical and family histories for these patients was not provided (Leedom 2016). The variant was identified in dbSNP (ID: rs786203650) as "With Likely pathogenic allele", and in ClinVar (classified as likely pathogenic by Ambry Genetics, Invitae, GeneDx and Counsyl). The variant was not identified in the Zhejiang University Database. The variant was identified in control databases in 1 of 209036 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in Latino population in 1 of 29610 chromosomes (freq: 0.00003), but not in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.683+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.