ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3897_3931dup (p.Glu1311fs) (rs1064793895)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478927 SCV000567296 pathogenic not provided 2015-07-15 criteria provided, single submitter clinical testing This duplication of 35 nucleotides in MSH6 is denoted c.3897_3931dup35 at the cDNA level and p.Glu1311AlafsX28 (E1311AfsX28) at the protein level. The surrounding sequence is AGAGG[dup35]AAGT. The duplication causes a frameshift, which changes a Glutamic Acid to an Alanine at codon 1311, and creates a premature stop codon at position 28 of the new reading frame. Even though this frameshift occurs in the 3' end of the gene, it is significant since the last 50 correct amino acids are replaced by 27 incorrect ones. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation and is located upstream of other frameshift variants; one specifically, MSH6 c.3984_3987dupGTCA, has been observed internally and published in several families with Lynch syndrome (Peterlongo 2003, Goldberg 2010, Raskin 2011). we consider this variant to be pathogenic.
Ambry Genetics RCV000491494 SCV000580094 pathogenic Hereditary cancer-predisposing syndrome 2014-09-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491494 SCV000690420 pathogenic Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
Invitae RCV001225210 SCV001397451 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Glu1311Alafs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 419474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the C-terminus of the MSH6 protein. Other variant(s) that disrupt this region (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 24440087, 26440929). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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