ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3549_3567dup (p.Ala1190delinsSerLysGlyThrTer) (rs63750767)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000129554 SCV000184335 pathogenic Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000074954 SCV000266096 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000524197 SCV000283830 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-07 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074954 SCV000592661 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Color RCV000129554 SCV000690421 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074954 SCV000695901 pathogenic Lynch syndrome 2019-07-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3939_3957dup19 (p.Ala1320SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249800 control chromosomes. c.3939_3957dup19 has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2003, Barnetson_2006, Chong_2009, Baglietto_2009, Kerr_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202115 SCV000888282 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202115 SCV000257288 pathogenic not provided no assertion criteria provided clinical testing

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