ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2150_2153del (p.Val717fs) (rs267608058)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162408 SCV000212744 pathogenic Hereditary cancer-predisposing syndrome 2017-07-21 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 RCV000162408 SCV000911350 pathogenic Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing
Counsyl RCV000411212 SCV000487839 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-11-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074720 SCV000592599 pathogenic Lynch syndrome 2013-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000202111 SCV000279100 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This deletion of four nucleotides in MSH6 is denoted c.2150_2153delTCAG at the cDNA level and p.Val717AlafsX18 (V717AfsX18) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAG[delTCAG]CACT. The deletion causes a frameshift, which changes a Valine to an Alanine at codon 717, and creates a premature stop codon at position 18 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2150_2153delTCAG, previously reported as MSH6 c.2147_2150delCAGT or 2149delTCAG, has been reported in several individuals with colorectal, ovarian, and/or endometrial cancer (Kolodner 1999, Talseth-Palmer 2010, Walsh 2011, van Lier 2012, Pagin 2013). Based on the currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074720 SCV000695800 pathogenic Lynch syndrome 2017-08-02 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2150_2153delTCAG (p.Val717Alafs) 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. This variant was found in 1/121546 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, ExAC indicates that the location is a low-quality site, therefore, this observation needs to be cautiously considered. Multiple publications cite the variant in affected individuals including one family (Talseth-Palmer_2010). 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) RCV000074720 SCV000107928 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524132 SCV000253775 pathogenic Hereditary nonpolyposis colon cancer 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val717Alafs*18) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in the literature in individuals affected with Lynch syndrome and associated cancers (PMID: 18566915, 10537275, 23652311, 20028993, 22006311, 23047549). ClinVar contains an entry for this variant (Variation ID: 89256). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202111 SCV000257219 pathogenic not provided no assertion criteria provided research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202111 SCV000889470 pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000074720 SCV000266092 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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