ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.943-2A>G (rs587779198)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076759 SCV000107800 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491601 SCV000580627 pathogenic Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing The c.943-2A>G intronic pathogenic mutation results from a A to G substitution two nucleotides upstream from coding exon 6 of the MSH2 gene. 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 RCV000544929 SCV000625486 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-06-01 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 and likely results in an absent or disrupted protein product. This variant has been reported in an individual affected with hereditary non-polyposis colorectal cancer (HNPCC) in the Leiden Open-source Variation Database (PMID: 21520333). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Counsyl RCV000663253 SCV000786478 likely pathogenic Lynch syndrome I 2018-05-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280659 SCV001467944 likely pathogenic Hereditary nonpolyposis colon cancer 2020-12-11 criteria provided, single submitter clinical testing Variant summary: MSH2 c.943-2A>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: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251250 control chromosomes. c.943-2A>G has been reported in the literature in an individual affected with Hereditary Nonpolyposis Colorectal Cancer (Jiang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353928 SCV000592481 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH2 c.943-2A>G variant was not identified in the literature. The variant was identified in the InSiGHT Colon Cancer Gene Variant Database (2X as “likely pathogenic”) and the ClinVar database (classified as a “likely pathogenic” variant by inSIGHT). The variant was not identified in any of the following databases: dbSNP, 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”, “Zhejiang Colon Cancer Database”, GeneInsight VariantWire database, and UMD. The c.943-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 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.

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