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

dbSNP: rs12476364

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076758	SCV000107799	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491758	SCV000580427	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	clinical testing	The c.943-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MSH2 gene. This variant has been detected in several probands whose family histories meet either Bethesda or Amsterdam I/II criteria for Lynch syndrome (Ambry internal data; Mangold E et al. Int. J. Cancer 2005;116(5):692-702; Rashid MU et al. Hered Cancer Clin Pract, 2019 Oct;17:29). In addition, this alteration has been identified in individuals exhibiting high microsatellite instability (MSI-H) and/or loss of MSH2 expression on immunohistochemistry (IHC) in their Lynch syndrome-associated tumors (Ambry internal data; Mangold E et al. J Pathol. 2005 Dec;207(4):385-95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Invitae	RCV000696831	SCV000825410	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 11151427, 15849733, 28874130; Invitae). ClinVar contains an entry for this variant (Variation ID: 91253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001531920	SCV001747251	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531920	SCV001983801	pathogenic	not provided	2021-10-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Mangold 2005a, Mangold 2005b, Rashid 2019); This variant is associated with the following publications: (PMID: 15849733, 31660093, 16216036, Chiang2021[Article], 33933134)
MGZ Medical Genetics Center	RCV002288573	SCV002578941	pathogenic	Lynch syndrome 1	2021-10-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288573	SCV004186749	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].