ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3450_3456del (p.Glu1151fs) (rs63751319)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074942 SCV000108156 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000219135 SCV000279616 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing This deletion of 7 nucleotides in MSH6 is denoted c.3840_3846delGGAGACT at the cDNA level and p.Glu1281LeufsX44 (E1281LfsX44) at the protein level. The normal sequence, with the bases that are deleted in braces, is GCCA{GGAGACT}ATTA. The deletion causes a frameshift which changes a Glutamic Acid to a Leucine at codon 1281, and creates a premature stop codon at position 44 of the new reading frame. Even though this frameshift occurs in the second to last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 80 amino acids are replaced by 43 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation, resulting in the loss of one of the two MSH2 binding sites (Kariola 2002). This variant, also known as MSH6 Q1280fsX1324 by alternate nomenclature, has been identified in at least two individuals with colorectal or endometrial cancer, one of whom met Bethesda guidelines for Lynch syndrome, and in one individual with an HNPCC-like phenotype (Barnetson 2006, Devlin 2008, Baglietto 2010). We consider this variant to be pathogenic.
Invitae RCV000627732 SCV000283824 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-21 criteria provided, single submitter clinical testing This sequence change deletes 7 nucleotides from exon 9 of the MSH6 mRNA (c.3840_3846delGGAGACT), causing a frameshift at codon 1281. This creates a premature translational stop signal in the penultimate exon of the MSH6 mRNA (p.Glu1281Leufs*44). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hereditary nonpolyposis colorectal cancer (Lynch syndrome) (PMID: 16807412, 18269114, 20028993). ClinVar contains an entry for this variant (Variation ID: 89474). A different deletion c.3959_3962del (p.Ala1320Glufsx6) downstream of this deletion that is not anticipated to result in nonsense mediated decay, is an Ashkenazi Jewish founder mutation (PMID: 21155762). In addition, there are other pathogenic mutations downstream of this deletion including another Askenazi Jewish founder mutation (PMID:21155762, 24323032). This indicates that the deleted amino acids residues are important for MSH6 protein function. 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). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000409718 SCV000488433 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-03-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491396 SCV000580217 pathogenic Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000074942 SCV000695892 pathogenic Lynch syndrome 2017-06-20 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3840_3846delGGAGACT (p.Glu1281Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. c.3938_3941dupTTCA, p.Gln1314fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120874 control chromosomes and has been reported in at least 2 affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color RCV000491396 SCV000905460 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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