Submissions for variant NM_007194.4(CHEK2):c.683+2T>C

dbSNP: rs781021132

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685127	SCV000812600	likely pathogenic	Familial cancer of breast	2024-01-21	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 breast cancer (PMID: 32885271). ClinVar contains an entry for this variant (Variation ID: 565542). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000685127	SCV002762813	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PM2_SUP, PS4_SUP
Myriad Genetics, Inc.	RCV000685127	SCV004043374	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357999	SCV001553622	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 c.683+2T>C variant was not identified in the literature. The variant was identified in dbSNP (ID: rs781021132) as “NA” and ClinVar (classified likely pathogenic by Invitae). The variant was identified in control databases in 1 of 207560 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 1 of 90562 chromosomes (freq: 0.00001), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.683+2T>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. However, only 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.