ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3530_3537dup (p.Glu1180fs) (rs587779295)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074949 SCV000108164 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000657357 SCV000779089 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing This duplication of eight nucleotides in MSH6 is denoted c.3920_3927dupATCTCCCA at the cDNA level and p.Glu1310IlefsX20 (E1310IfsX20) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GCTA[dupATCTCCCA]GAGG. The duplication causes a frameshift which changes a Glutamic Acid to an Isoleucine at codon 1310, and creates a premature stop codon at position 20 of the new reading frame. It is predicted to cause loss of normal protein function through protein truncation as the last 51 amino acids are lost and replaced with 19 incorrect amino acids. The disrupted region at the end of the gene is located within the ATPase domain and the MSH2 binding site (Kariola 2002, Warren 2007, Kansikas 2011). MSH6 c.3920_3927dupATCTCCCA has been reported in at least one family with Lynch syndrome (Sjursen 2016). We consider this variant to be pathogenic.
Invitae RCV000692457 SCV000820282 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Glu1310Ilefs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89481). A different truncation (p.Leu1330Valfs*12) that lies downstream of this variant has been determined to be pathogenic (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 24440087). This suggests that deletion of this region of the MSH6 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657357 SCV000889504 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing

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