Submissions for variant NM_007194.4(CHEK2):c.908+1G>C

dbSNP: rs587781699

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589468	SCV000698822	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The c.908+1G>C (aka IVS8+1G>C) in a CHEK2 gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from control datasets of ExAC and gnomAD (~29770 and 196838 chrs tested, respectively). The variant has not, to our knowledge, been reported in affected individuals via publications or cited as by a reputable database/clinical laboratory. Alteration on the same nucleotide, c.908+1G>A, has been reported in at least 3 BrC patients (Leedom, 2016) with classification of Likely Pathogenic. Taken together, the variant was classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867911	SCV002274489	likely pathogenic	Familial cancer of breast	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with prostate cancer (PMID: 31214711, 32832836). ClinVar contains an entry for this variant (Variation ID: 496347). Studies have shown that disruption of this splice site results in skipping of exon 8 , and produces a non-functional protein and/or introduces a premature termination codon (Invitae). 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.
Myriad Genetics, Inc.	RCV001867911	SCV004045113	likely pathogenic	Familial cancer of breast	2023-06-27	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.