ClinVar Genomic variation as it relates to human health

Multifactorial likelihood analysis posterior probability >0.99

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 >=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.

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.

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.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID:28531214]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:14961575].

This missense variant replaces leucine with proline at codon 449 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant retains 10% of wild-type mismatch repair activity (PMID: 28531214, 31965077). 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 ten 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 Pathogenic.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 449 of the MSH6 protein (p.Leu449Pro). This variant is present in population databases (rs63750741, gnomAD 0.003%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 16283884). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. For these reasons, this variant has been classified as Pathogenic.