ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1346T>C (p.Leu449Pro) (rs63750741)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491070 SCV000580282 pathogenic Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Structural Evidence
Color RCV000491070 SCV000905449 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-25 criteria provided, single submitter clinical testing
Counsyl RCV000576688 SCV000677746 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-05-02 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074651 SCV000107853 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000627730 SCV000261013 pathogenic Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 449 of the MSH6 protein (p.Leu449Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs63750741, 0.003%) and has been reported  to segregate with Lynch syndrome-associated cancers  in a large multigenerational family (PMID: 16283884). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MSH6 gene (PMID: 23621914) all suggest that this missense change is likely to be pathogenic, Furthermore, tumors of affected individuals carrying this variant showed no expression of MSH6  (PMID: 16283884). In summary, this is a rare missense variant that has been shown to segregate with disease in a large family. For these reasons it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000074651 SCV000731318 pathogenic Lynch syndrome 2017-03-03 criteria provided, single submitter clinical testing The p.Leu449Pro variant in MSH6 has been reported in >10 individuals with Lynch syndrome-associated cancers from a large multigenerational Swedish family (Ceder quist 2004, Cederquist 2005). In addition, the majority of tumors sampled from t hese individuals showed microsatellite instability and lacked MSH6 expression. T his variant has also been identified in 2/66718 of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750 741). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. Furthermore, this variant was classified as Patho genic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV 000107853). In summary, the p.Leu449Pro variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon segr egation studies and low frequency in controls.

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