Submissions for variant NM_000251.3(MSH2):c.367-1G>A

dbSNP: rs267607925

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076577	SCV000107617	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491499	SCV000580426	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-07-17	criteria provided, single submitter	clinical testing	The c.367-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 3 of the MSH2 gene. This alteration has been reported in a family meeting Amsterdam criteria, in which the tumor of the proband exhibited high/stable microsatellite instability (Wolf B et al. Wien Klin Wochenschr. 2005;117(7-8):269-77). This nucleotide position is highly conserved on sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of 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.
Invitae	RCV001377879	SCV001575326	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-19	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: 91075). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15926618, 25980754). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the MSH2 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 MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Myriad Genetics, Inc.	RCV003452937	SCV004186626	likely pathogenic	Lynch syndrome 1	2023-07-27	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.