ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3556+1del (rs1064793489)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480410 SCV000566246 pathogenic not provided 2015-04-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 IVS6+1delG or c.3556+1delG and consists of a deletion of one nucleotide at the +1 position of intron 6. The normal sequence, with the base that is deleted in brackets, is TCAG[g]tgag, 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.3556+1delG to be a pathogenic variant.
Ambry Genetics RCV000491243 SCV000580371 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The c.3556+1delG intronic variant, located in intron 6 of the MSH6 gene, results from a deletion of one nucleotide within intron 6 of the MSH6 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, the native donor splice site is abolished, with a new donor site shifted five nucleotides upstream resulting in a translational frameshift with a predicted alternate stop codon; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586064 SCV000695872 likely pathogenic Lynch syndrome 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3556+1delG variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict loss/weakening effect on the canonical splicing donor site and ESEfinder predict changes of binding motifs for RNA splicing enhancers. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 120962 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

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