Submissions for variant NM_000251.3(MSH2):c.1277-1G>C

dbSNP: rs267607948

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076098	SCV000107120	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV001010704	SCV001170937	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-03-04	criteria provided, single submitter	clinical testing	The c.1277-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 8 of the MSH2 gene. This alteration has been reported in the germline of one German individual diagnosed with MSI-high colorectal cancer demonstrating the loss of MSH2 protein (Mangold E et al. J. Pathol., 2005 Dec;207:385-95). 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.	RCV003452818	SCV004186674	likely pathogenic	Lynch syndrome 1	2023-08-01	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.