ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3557-4dup (rs267608102)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074886 SCV000108099 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Ambry Genetics RCV000162507 SCV000212898 likely benign Hereditary cancer-predisposing syndrome 2012-11-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc RCV000162507 SCV000690369 benign Hereditary cancer-predisposing syndrome 2014-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000584641 SCV001360589 benign not specified 2019-02-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3557-4dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.15 in 27938 control chromosomes in the gnomAD database, including 314 homozygotes. The observed variant frequency is approximately 1075 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. c.3557-4dupT has been reported in the literature in multiple affected individuals and also, a large number of controls and has been described as a polymorphism (Wasielewski_2010, Vahteristo_2005, Charames_2000). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000584641 SCV000691940 benign not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000613784 SCV000734221 benign Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing

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