ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1754T>C (p.Leu585Pro) (rs587779220)

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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 RCV000491054 SCV000580096 likely pathogenic Hereditary cancer-predisposing syndrome 2017-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
GeneDx RCV000219463 SCV000279553 likely pathogenic not provided 2016-06-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1754T>C at the cDNA level, p.Leu585Pro (L585P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). MSH6 Leu585Pro has been observed in at least two individuals with Lynch syndrome related cancers (Kantelinen 2012, Frolova 2015). Kantelinen et al. (2012) completed two functional assays for MSH6 Leu585Pro; an in vitro based functional assay which showed this variant to be deficient in mismatch repair activity and a western blot analysis which showed it results in a dramatic reduction of the MSH6 protein. This variant 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 Leu585Pro occurs at a position that is conserved across species and is located in the MutS domain II (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider MSH6 Leu585Pro to be a likely pathogenic variant.
Invitae RCV000791380 SCV000551070 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 585 of the MSH6 protein (p.Leu585Pro). 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 individuals affected with colorectal cancer and endometrial cancer (PMID: 22581703, 21520333). ClinVar contains an entry for this variant (Variation ID: 89220). Experimental studies have shown that this missense change leads to reduced expression and defective mismatch repair activity of the MSH6 protein (PMID: 22581703). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000074683 SCV000887368 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1754T>C has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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