ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.457+2dup (rs876661224)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214122 SCV000279835 uncertain significance not specified 2016-01-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 IVS2+2dupT or c.457+2dupT and consists of a duplication of one nucleotide at the +2 position in intron 2 of the MSH6 gene. The normal sequence with the bases that are duplicated in braces is CAGg{t}aaga. Multiple in silico models predict this variant to damage or destroy the nearby natural 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. MSH6 c.457+2dupT 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. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotide that is duplicated is conserved across species. Based on the currently available information, we consider MSH6 c.457+2dupT to be a variant of uncertain significance.
Invitae RCV000456400 SCV000551122 uncertain significance Lynch syndrome 2016-05-27 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the MSH6 mRNA. It does not directly change the encoded amino acid sequence of the MSH6 protein, but it affects several highly conserved nucleotides in the +3 to +5 positions within the consensus splice site of the intron (PMID: 9536098). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. Nucleotide substitutions that affect the +5 position are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

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