ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1304T>C (p.Leu435Pro) (rs63751405)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128873 SCV000172730 likely pathogenic Hereditary cancer-predisposing syndrome 2014-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),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
GeneDx RCV000214282 SCV000279609 likely pathogenic not provided 2016-01-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1304T>C at the cDNA level, p.Leu435Pro (L435P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has been observed in at least one endometrial cancer patient whose tumor exhibited microsatellite instability (MSI-H) and absence of MSH6 protein expression (Hampel 2006, Kantelinen 2012). In addition, this variant has been predicted to result in skipping of exon 4, and has demonstrated protein instability and almost complete mismatch repair deficiency in vitro (Hampel 2007, Kantelinen 2012). MSH6 Leu435Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Leu435Pro occurs at a position that is conserved across species and is located in the MSH2 binding site and domain V of the MutS domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH6 Leu435Pro to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074648 SCV000107850 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000074648 SCV000283710 uncertain significance Lynch syndrome 2016-12-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 435 of the MSH6 protein (p.Leu435Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with endometrial cancer (PMID: 16885385). ClinVar contains an entry for this variant (Variation ID: 89186). Multiple protein prediction methods suggest that this variant is disruptive for MSH6 protein function (PMID: 23621914, 22290698). Experimental evidence from cell culture studies demonstrate that this variant is associated with protein instability and a lack of mismatch repair activity (PMID: 22581703). One study observed a correlation between this variant and loss of exon 4 from MSH6 mRNA in patient blood, suggesting this variant may disrupt protein function through a splicing defect (PMID: 17909073). In summary, this variant is a rare missense change that has been shown to disrupt protein function. While this variant is not currently present in the general population and has been reported in the literature in an affected individual, the available evidence is insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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