Submissions for variant NM_007194.4(CHEK2):c.909-2A>G

dbSNP: rs1555915589

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576712	SCV000677832	likely pathogenic	Familial cancer of breast	2017-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000584150	SCV000689745	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-23	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 8 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 an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576712	SCV000757310	likely pathogenic	Familial cancer of breast	2022-09-06	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. 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: 487405). Disruption of this splice site has been observed in individual(s) with a Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 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).
Ambry Genetics	RCV000584150	SCV001180108	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-12-27	criteria provided, single submitter	clinical testing	The c.909-2A>G intronic variant results from an A to G substitution two nucleotides upstream from N/A in the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.	RCV000576712	SCV004020129	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.
CeGaT Center for Human Genetics Tuebingen	RCV003886415	SCV004704346	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CHEK2: PVS1:Strong, PM2, PS4:Supporting
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV004732484	SCV005340992	likely pathogenic	Bone osteosarcoma		criteria provided, single submitter	clinical testing	This canonical splice-site variant is likely to cause aberrant splicing leading to either the formation of a truncated protein product or the transcript may undergo nonsense-mediated mRNA decay. Biallelic and monoallelic variants in CHEK2 have been associated with increased risk for hereditary cancers, osteosarcoma, somatic (MIM# 259500), prostate cancer, somatic (MIM# 176807) and tumor predisposition syndrome 4, breast/prostate/colorectal (MIM# 609265). This variant in a germline heterozygous state has been previously reported in a patient with colorectal cancer (ClinVar ID: 487405; Yurgelun et al. 2015). Bi-allelic germline variants in CHEK2 has recently been reported in patients with multiple breast cancers and multiple meningiomas (Bottillo et al. 2023).