ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.687_688insT (p.Ala230fs)

dbSNP: rs63750364
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491983 SCV000580433 pathogenic Hereditary cancer-predisposing syndrome 2014-01-28 criteria provided, single submitter clinical testing ​The c.687_688insT pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from the insertion of T between nucleotide positions 687 and 688, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000503686 SCV000592475 pathogenic Lynch syndrome no assertion criteria provided clinical testing The MSH2 p.Ala230CysfsX2variant was not identified in the literature nor was it identified in 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”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and UMD. The variant was also not previously identified by our laboratory. The p.Ala230CysfsX2 insertion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 230 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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