ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.571_573delCTC (rs587779165)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076643 SCV000107678 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
GeneDx RCV000497286 SCV000211232 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MSH2 is denoted c.571_573delCTC at the cDNA level and p.Leu191del (L191del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TCTC[delCTC]ATCC. MSH2 Leu191del has been observed in families meeting Amsterdam I or II criteria for Lynch syndrome and demonstrating absence of MSH2 and MSH6 protein expression in tumors (Arnold 2009, Sjursen 2010). Internal observations have also demonstrated co-segregation of MSH2 Leu191del with Lynch syndrome associated tumors. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). In silico analyses predict that this is probably damaging to protein structure and function. This deletion occurs in a region that is conserved across species and is located in the Connector domain (L?tzen 2008, Kansikas 2011). Based on currently available information and internal data, we consider this deletion to be pathogenic.
Invitae RCV000684796 SCV000284174 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-05-08 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 3 of the MSH2 mRNA (c.571_573delCTC). This leads to the deletion of 1 amino acid residue in the MSH2 protein (p.Leu191del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Lynch syndrome in several families (PMID: 22949379, 20587412, 19267393) and has been observed in an individual affected with colon cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 91139). Multifactorial likelihood analyses incorporating genetic and bioinformatic data along with tumor characteristics indicate that this variant is likely to be pathogenic (PMID: 19267393, 24362816) The leucine at codon 191 falls in the connector domain of the MSH2 protein, and the variants within this domain have been reported to be important for the DNA mismatch repair function of MSH2 (PMID: 18822302). Experimental studies analyzing the effect of this Leu191 deletion on MSH2 function have not been reported. 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.
Ambry Genetics RCV000160632 SCV000580517 pathogenic Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing The c.571_573delCTC pathogenic mutation (also known as p.L191del) is located in coding exon 3 of the MSH2 gene. This pathogenic mutation results from an in-frame deletion of 3 nucleotides between positions 571 and 573. This results in the deletion of a leucine residue at codon 191. This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46(2):107-15; available at []). This mutation has also been reported in six unrelated HNPCC families with five of the families having absent MSH2 and MSH6 staining on IHC (Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). In addition, it was identified in 1/10030 patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). Based on the available evidence, c.571_573delCTC is classified as a pathogenic mutation.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076643 SCV000592469 likely pathogenic Lynch syndrome criteria provided, single submitter clinical testing

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