ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.5C>T (p.Ala2Val) (rs587778521)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561626 SCV000662316 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512708 SCV000608935 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing
Color RCV000561626 SCV000685106 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Counsyl RCV000410801 SCV000487976 uncertain significance Lynch syndrome I 2015-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000512708 SCV000293266 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.5C>T at the cDNA level, p.Ala2Val (A2V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). MSH2 Ala2Val was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MSH2 Ala2Val was not observed in large population cohorts (Lek 2016). MSH2 Ala2Val is located in the mismatch binding domain and is an N-acetylalanine residue (Lutzen 2008, Kansikas 2011, Van Damme 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Ala2Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000121557 SCV000085751 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000168363 SCV000219053 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2 of the MSH2 protein (p.Ala2Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 134840). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121557 SCV000601487 uncertain significance not specified 2017-02-24 criteria provided, single submitter clinical testing

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