ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.403C>G (p.Leu135Val) (rs193096019)

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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 RCV000166792 SCV000217606 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166792 SCV000685089 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000235557 SCV000292812 uncertain significance not specified 2017-02-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.403C>G at the cDNA level, p.Leu135Val (L135V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Leu135Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu135Val occurs at a position that is conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu135Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000546078 SCV000625423 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 135 of the MSH2 protein (p.Leu135Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs193096019, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 187103). 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: "Benign"; Align-GVGD: "Class C15"). 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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