ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.645+3A>G (rs587779168)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000419965 SCV000530721 likely benign not specified 2016-08-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000627695 SCV000548191 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-03 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587779168, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91157). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional 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.
Ambry Genetics RCV000491694 SCV000580438 likely benign Hereditary cancer-predisposing syndrome 2018-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intronic alteration with no splicing impact by rt-pcr analysis or other splicing assay,In silico models in agreement (benign),RNA Studies
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000419965 SCV000731402 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing The c.645+3A>G variant in MSH2 has not been previously reported in individuals w ith Lynch syndrome but has been identified in 1/8640 of East Asian chromosomes b y the Exome Aggregation Consortium (ExAC,; dbSNP rs587779168). This variant is located in the 5' splice region. Computational too ls do not suggest an impact to splicing. However, this information is not predic tive enough to rule out pathogenicity. In addition, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000107696.2). In summary, the clinical significance of the c.645+3A>G variant is uncertain.
Color RCV000491694 SCV000908279 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing

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