ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4002-2A>G (rs878853745)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772337 SCV000905506 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Invitae RCV000231436 SCV000283838 likely pathogenic Hereditary nonpolyposis colon cancer 2018-07-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 9) of the MSH6 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 been observed in an individual affected with colon cancer (PMID: 29237405). ClinVar contains an entry for this variant (Variation ID: 237206). 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 nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing by shifting the acceptor splice site 1 nucleotide upstream, thereby creating a frameshift and an early termination codon. This prediction has not been confirmed by published transcriptional studies. 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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