ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1387-2del

dbSNP: rs2104082025
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001871953 SCV002317217 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-01-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358615 SCV001554402 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH2 c.1387-2delA variant was not identified in the literature nor was it identified in the following databases: dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer/Zhejiang Colon Cancer/Mismatch Repair Genes Variant/MMR Gene Unclassified Variants/and Insight Hereditary Tumors databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1387-2delA 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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