ClinVar Miner

Submissions for variant NM_000179.3(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
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 colorectal neoplasms 2020-10-05 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.
Ambry Genetics RCV000491070 SCV000580282 pathogenic Hereditary cancer-predisposing syndrome 2019-03-25 criteria provided, single submitter clinical testing The p.L449P pathogenic mutation (also known as c.1346T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1346. The leucine at codon 449 is replaced by proline, an amino acid with similar properties. This alteration has been reported as a Swedish founder mutation after showing strong segregation in numerous individuals affected with Lynch syndrome in a large family. Tumor studies for many of these individuals revealed high microsatellite instability and loss of MSH6 staining on immunohistochemistry (IHC) (Cederquist K et al. Int J Cancer. 2004 Apr 10;109(3):370-6; Cederquist K et al.Clin Genet. 2005 Dec;68(6):533-41). In addition, this mutation has been identified in 4/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). It has also been detected in several individuals in our clinical cohort affected with Lynch syndrome and their tumor studies revealed loss of MSH6 staining on IHC and/or high microsatellite instability (Ambry internal data). Based on internal structural analysis, p.L449P would directly affect DNA binding interactions of the mismatch binding domain, at a minimum, and may lead to gross misfolding to alleviate clashes (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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 B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, p.L449P is interpreted as a disease-causing mutation.
Counsyl RCV000576688 SCV000677746 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-05-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000074651 SCV000731318 pathogenic Lynch syndrome 2019-04-19 criteria provided, single submitter clinical testing The p.Leu449Pro variant in MSH6 has been reported in >10 individuals with MSH6-associated cancers from a large multigenerational Swedish family (Cederquist 2004, Cederquist 2005). In addition, the majority of tumors sampled from these individuals showed microsatellite instability and lacked MSH6 expression. This variant has also been identified in 3/113542 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant was classified as Pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000107853). In summary, the p.Leu449Pro variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon segregation studies and low frequency in controls. ACMG/AMP Criteria applied: PP1_Strong, PM2, PP3, PS3_Strong.
Color Health, Inc RCV000491070 SCV000905449 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-01 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 449 of the MSH6 protein in the MSH2 binding domain. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies has shown that this variant impairs DNA mismatch repair (MMR) activity (PMID: 31965077) and results in higher mutagenesis compared to the MSH6-proficient cells (PMID: 28531214). This variant has been reported in four individuals affected double primary Lynch syndrome (LS) associated cancers (PMID: 14961575) in Sweden. Additionally, this variant has been reported in 10 individuals with LS associated cancers from a large Swedish family (PMID: 16283884). This variant has been identified in 3/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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