ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3939_3957dup (p.Ala1320delinsSerLysGlyThrTer) (rs63750767)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129554 SCV000184335 pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000129554 SCV000690421 pathogenic Hereditary cancer-predisposing syndrome 2015-07-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074954 SCV000592661 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
GeneDx RCV000202115 SCV000211388 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing This duplication of 19 nucleotides is denoted MSH6 c.3939_3957dup19 at the cDNA level and p.Ala1320SerfsX5 (A1320SfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is TTAT[dup19]GCAA. The duplication causes a frameshift, which changes an Alanine to a Serine at codon 1320, and creates a premature stop codon at position 5 of the new reading frame resulting in the last 41 amino acids being replaced by four incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. MSH6 c.3939_3957dup19 has been reported in association with Lynch syndrome (Goodfellow 2003, Barnetson 2006, Hampel 2008, Chong 2009, Yurgelun 2015, Kerr 2016, Nowak 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074954 SCV000695901 pathogenic Lynch syndrome 2017-11-24 criteria provided, single submitter clinical testing Variant Summary: The c.3939_3957dup19 (p.Ala1320SerfsX5) results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein, which is a commonly known mechanism for disease. The variant is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/244848 chrs tested), but has been reported in numerous affected individuals. Additionally, multiple reputable clinical labs and databases have classified the variant as "pathogenic". Taken together, this variant has been classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074954 SCV000108169 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524197 SCV000283830 pathogenic Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change inserts 19 nucleotides in exon 9 of the MSH6 mRNA (c.3939_3957dup), causing a frameshift at codon 1320. This creates a premature translational stop signal within the last 15 codons in the penultimate exon of the MSH6 mRNA (p.Ala1320Serfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the MSH6 protein. This variant has been reported in individuals with colorectal cancer, and families affected with Lynch syndrome (PMID: 18809606, 19459153, 25980754, 27456091, 26845104). It has also been reported in an individual affected with breast cancer (PMID: 25186627), and individuals affected with endometrial and ovarian cancer (PMID: 26552419, 26681312). ClinVar contains an entry for this variant (Variation ID: 89486). A different MSH6 variant, c.3959_3962delCAAG (p.Ala1320Glufs*6), creating a frameshift at the same Ala1320 amino acid, has been reported as an Ashkenazi Jewish founder mutation known to cause Lynch syndrome (PMID: 21155762). While no functional studies have been performed to test the effects of this particular variant on MSH6 protein function or stability, it is expected to delete the C-terminal portion of the conserved MutS domain (PMID: 17531815, 24100870). This domain is necessary for the heterodimerization of MSH6 and MSH2 (PMID: 15952900, 16464007). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202115 SCV000257288 pathogenic not provided no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202115 SCV000888282 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000074954 SCV000266096 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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