Submissions for variant NM_000251.3(MSH2):c.1386+1G>T

dbSNP: rs267607957

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076139	SCV000107154	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV002390223	SCV002702601	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The c.1386+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 8 of the MSH2 gene. This alteration (referred to as IVS8+1G>T) has been reported in two French HNPCC families (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13) as well as in individuals whose Lynch syndrome-related tumors demonstrated high microsatellite instability (MSI-H) and loss of MSH2 by IHC analysis (van der Post RS et al. J Med Genet, 2010 Jul;47:464-70). (Overbeek LI et al. Br J Cancer, 2007 May;96:1605-12). 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 donor site. 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	RCV002514350	SCV003524641	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 17453009, 20591884). ClinVar contains an entry for this variant (Variation ID: 90643). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 16395668, 19669161; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452829	SCV004186600	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.
Color Diagnostics, LLC DBA Color Health	RCV002390223	SCV004356680	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 8 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals and families affected with Lynch syndrome and Lynch syndrome-associated cancers (PMID: 12624141, 17453009, 20591884, 21642682, 26300997, 30723297, 31118792, 30877237). In several of these individuals, tumors displayed loss of MSH2 protein expression via immunohistochemistry analysis and high microsatellite instability (PMID: 17453009, 20591884, 30877237). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723646	SCV001957745	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723646	SCV001970212	pathogenic	not provided		no assertion criteria provided	clinical testing