ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1077-3C>T (rs758182607)

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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 RCV000221368 SCV000276806 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000235545 SCV000293897 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1077-3C>T or IVS6-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 6 of the MSH2 gene. Multiple in silico models predict this variant to weaken the nearby natural acceptor 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.1077-3C>T 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 cytosine (C) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether MSH2 c.1077-3C>T is pathogenic or benign.
Invitae RCV000629733 SCV000750689 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-06 criteria provided, single submitter clinical testing This sequence change falls in intron 6 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 (rs758182607, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 232625). 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.
Color RCV000221368 SCV000903425 likely benign Hereditary cancer-predisposing syndrome 2015-04-29 criteria provided, single submitter clinical testing

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