Submissions for variant NM_000251.3(MSH2):c.2211-2A>G

dbSNP: rs267608001

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700706	SCV000829473	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-12-15	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. Donor and acceptor splice site variants 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 has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 29164703, 3258778,18713544). This variant is also known as IVS13-2A>G and g.2211-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 433899). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 13 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251330	SCV001426887	pathogenic	Hereditary nonpolyposis colon cancer	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2211-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251220 control chromosomes (gnomAD). c.2211-2A>G has been reported in the literature in individuals affected with Lynch syndrome, colon cancer, endometrial cancer and urinary tract cancer (Urakami_2018, Ren_2020, Wischhusen_2020, Yamashita_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002431453	SCV002728306	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-21	criteria provided, single submitter	clinical testing	The c.2211-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 14 in the MSH2 gene. This variant (referred to as IVS13-2A>G) has been reported in one individual diagnosed with ureter cancer exhibiting loss of the MSH2 and MSH6 proteins on immunohistochemistry (IHC) and also with colorectal cancer (Urakami S et al. Int J Urol, 2018 02;25:151-156). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH2 and MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ren C et al. Cancer Biol Med, 2020 May;17:458-467; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003449405	SCV004186751	likely pathogenic	Lynch syndrome 1	2023-08-08	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504524	SCV000592544	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.2211-2A>G variant was identified in dbSNP (ID: rs 267608001) “With likely pathogenic allele”. It was not identified in the literature nor was it identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database or UMD databases. The c.2211-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.