ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1618C>A (p.Leu540Ile) (rs201996928)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034493 SCV000043356 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000583196 SCV000690208 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000034493 SCV000566410 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1618C>A at the cDNA level, p.Leu540Ile (L540I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). MSH6 Leu540Ile was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). MSH6 Leu540Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu540Ile occurs at a position that is conserved across species and is located within the connector domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Leu540Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000693805 SCV000821688 uncertain significance Hereditary nonpolyposis colon cancer 2018-02-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 540 of the MSH6 protein (p.Leu540Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs201996928, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 41589). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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