Submissions for variant NM_000251.3(MSH2):c.1077-2A>G

dbSNP: rs267607943

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076024	SCV000107044	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491149	SCV000580643	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	The c.1077-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the MSH2 gene. This intronic mutation has previously been reported in a German patient whose personal and family history was suspicious for HNPCC/Lynch syndrome and whose tumor was MSI-H with absent MSH2/MSH6 proteins on IHC, as well as a patient with endometrial cancer whose tumor had absent MSH2/MSH6 proteins on IHC with a family history meeting Amsterdam criteria (Mueller-Koch Y et al. Gut 2005 Dec;54(12):1733-40; Ambry internal data). This variant was also reported in a male proband age 47 with a family history of urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 Jan;29:193-199). 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. 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	RCV000529751	SCV000625225	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 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 Lynch syndrome-associated cancers (PMID: 15849733, 15955785, 20388775, 24278394, 37314251). ClinVar contains an entry for this variant (Variation ID: 90529). 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. This variant disrupts the c.1077-2G nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 14970868, 24278394, 31615790; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811351	SCV002050172	likely pathogenic	not provided	2021-05-08	criteria provided, single submitter	clinical testing	The MSH2 c.1077-2A>G variant (rs267607943) is reported in the literature in multiple individuals affected with Lynch syndrome (Mueller-Koch 2005, Mangold 2005, Nagasaka 2010, Wischhusen 2020). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 6, which is likely to negatively impact gene function. Additionally, different variants at this splice acceptor site (c.1077-2A>G, c.1077-2A>T, c.1077-1G>A, c.1077-1G>T and c.1077-1G>C) have been reported in individuals with Lynch syndrome. Based on available information, this variant is considered to be likely pathogenic. References Mueller-Koch et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005 Dec;54(12):1733-40. PMID: 15955785 Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. PMID: 15849733 Nagasaka T et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. Cancer Res. 2010 Apr 15;70(8):3098-108. PMID: 20388775 Wischhusen JW et al. Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. Cancer Epidemiol Biomarkers Prev. 2020 Jan;29(1):193-199. PMID: 31615790
Myriad Genetics, Inc.	RCV003452802	SCV004188169	pathogenic	Lynch syndrome 1	2023-07-31	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].