ClinVar Miner

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

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Total submissions: 3
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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 2019-09-26 criteria provided, single submitter clinical testing 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;Rarity in general population databases (dbsnp, esp, 1000 genomes)
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.
Invitae RCV000791437 SCV000283710 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-27 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 observed in an individual affected with endometrial cancer (PMID: 16885385). It has also been observed to segregate with Lynch syndrome-related cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 89186). This variant has been reported to affect MSH6 mRNA expression and/or protein stability/function (PMID: 17909073, 22581703). 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.

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