Submissions for variant NM_000251.3(MSH2):c.943-1G>A

dbSNP: rs12476364

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076757	SCV000107798	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000532450	SCV000625485	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 91252). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 11151427, 20233461, 26866578). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV002371918	SCV002687165	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The c.943-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the MSH2 gene. This variant was reported in an individual who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability (Pistorius SR et al. Int J Colorectal Dis. 2000 Nov;15(5-6):255-63). This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression by immunohistochemistry (Ambry internal data). This variant has also been identified as somatic in conjunction with a somatic pathogenic MSH2 variant in a tumor that demonstrated high microsatellite instability and loss of MSH2/MSH6 expression by immunohistochemistry (Haraldsdottir S et al. Gastroenterology. 2014 Dec;147(6):1308-1316.e1; Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003452979	SCV004186731	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].