ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2635-2A>C (rs1114167818)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491293 SCV000580612 likely pathogenic Hereditary cancer-predisposing syndrome 2016-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000819458 SCV000960118 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 15) of the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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: 428546). Other sequence changes at this splice site have been observed in individuals affected with clinical features of Lynch syndrome (PMID: 21286823, 27601186, 15849733, 12624141). 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.

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