ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.942+3A>G (rs193922376)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479341 SCV000565825 uncertain significance not provided 2016-12-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.942+3A>G or IVS5+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. Multiple in silico models predict this variant to damage the nearby natural splice donor site, and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 c.942+3A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is conserved across species. Based on currently available information, it is unclear whether MSH2 c.942+3A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000530947 SCV000625483 uncertain significance Hereditary nonpolyposis colon cancer 2017-10-03 criteria provided, single submitter clinical testing This sequence change falls in intron 5 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 not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 418625). 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479341 SCV001134379 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing

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