ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.260+2_260+3delinsAG (rs1064794075)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479300 SCV000567737 pathogenic not provided 2015-08-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.260+2_260+3delTAinsAG or IVS1+2_IVS1+3delTAinsAG and consists of a TA>AG substitution at the +2 position of intron 1 of the MSH6 gene. The normal sequence, with the bases that are deleted in braces and the bases that are inserted in brackets, is CAGg[ta][ag]gcgg, where the capital letters are exonic and lowercase are intronic. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider MSH6 c.260+2_260+3delTAinsAG to be a pathogenic variant.
Ambry Genetics RCV000491081 SCV000580219 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-19 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 RCV000629811 SCV000750767 likely pathogenic Hereditary nonpolyposis colon cancer 2017-10-31 criteria provided, single submitter clinical testing This sequence change affects donor splice site in intron 1 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 419737). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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