ClinVar Miner

Submissions for variant NM_000179.2 (MSH6):c.3984_3987dupGTCA (p.Leu1330Valfs) (rs267608121)

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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 RCV000131963 SCV000187020 pathogenic Hereditary cancer-predisposing syndrome 2018-03-25 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 RCV000131963 SCV000685473 pathogenic Hereditary cancer-predisposing syndrome 2016-06-05 criteria provided, single submitter clinical testing
Counsyl RCV000576365 SCV000677790 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-11-28 criteria provided, single submitter clinical testing
GeneDx RCV000202165 SCV000211390 pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing This duplication of four nucleotides in MSH6 is denoted c.3984_3987dupGTCA at the cDNA level and p.Leu1330ValfsX12 (L1330VfsX12) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ATCA[dupGTCA]CTAC. The duplication causes a frameshift which changes a Leucine to a Valine at codon 1330, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function though protein truncation as the last 31 amino acids are lost and replaced with 11 incorrect amino acids. The disrupted region at the end of the gene is located within the ATPase domain and an MSH2 binding site (Kariola 2002, Warren 2007, Kansikas 2011). MSH6 c.3984_3987dupGTCA, also published as MSH6 3987insGTCA and 3987ins4, has been reported in association with Lynch syndrome and is considered to be a pathogenic founder variant in the Ashkenazi Jewish population (Peterlongo 2003, Goldberg 2010, Raskin 2011, Salo-Mullen 2015). This variant has also been reported in trans with another pathogenic MSH6 variant in at least one family with constitutional mismatch repair deficiency syndrome (Bakry 2014). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000576365 SCV000840014 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-09-08 criteria provided, single submitter clinical testing This c.3984_3987dup variant in the MSH6 gene has been reported in one HNPCC patient (PMID16237223), two endometrial cancer patients (PMID15236168) and three related CRC patients with segregation in two generations (PMID14520694). In addition, a case control study identified this variant in 8/2685 CRC cases, 2/337 endometrial cancer cases and 1/330 control. PMID19851887 suggest this variant to be a founder variant for Ashkenazi Jews. This variant is predicted to cause a frameshift and create a premature stop codon. Based upon above evidence, this c.3984_3987dupGTCA variant in the MSH6 gene is classified pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074964 SCV000695904 pathogenic Lynch syndrome 2017-05-18 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3984_3987dupGTCA (p.Leu1330Valfs) 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.3991C>T, p.Arg1331X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/123518 control chromosomes at a frequency of 0.0000324, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported in numerous patients and families in the literature, including several compound heterozygotes with CMMRD. The variant has been described in the literature as an Ashkenazi Jewish founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074964 SCV000108179 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524201 SCV000218775 pathogenic Hereditary nonpolyposis colon cancer 2018-11-08 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 9 of the MSH6 mRNA (c.3984_3987dupGTCA), causing a frameshift at codon 1330. This creates a premature translational stop signal in the last exon of the MSH6 mRNA (p.Leu1330Valfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MSH6 protein. Loss-of-function variants in MSH6 are known to be pathogenic. This particular variant has been reported in individuals affected with colorectal, endometrial and pancreatic cancer (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 26440929). This variant was reported to segregate with colorectal cancer in a family: the variant was observed in the affected father and affected paternal uncle of the proband while absent in a sister without colorectal cancer (PMID: 14520694). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 24440087) and is considered a founder mutation in the Ashkenazi Jewish population (PMID: 19851887, 21155762). This variant is also known as 3987ins4 in the literature. ClinVar contains an entry for this variant (Variation ID: 89496). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202165 SCV000257291 pathogenic not provided no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202165 SCV000601594 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing

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