ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.646-4A>G (rs587779974)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759119 SCV000149447 uncertain significance not provided 2014-01-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 IVS3-4A>G or c.646-4A>G and consists of a A>G nucleotide substitution at the -4 position of intron 3 of the MSH2 gene. Multiple in silico prediction programs predict this variant to weaken the nearby natural acceptor site, and to possibly cause abnormal gene splicing. The base is well-conserved throughout evolution. This variant has not, to our knowledge, been published in the literature as pathogenic or benign and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on the currently available information, we consider MSH2 c.646-4A>G to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759119 SCV000888228 uncertain significance not provided 2018-02-14 criteria provided, single submitter clinical testing
Invitae RCV000796001 SCV000935487 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-04 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127649). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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 RCV001025294 SCV001187456 likely benign Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification

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