ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3160A>T (p.Ile1054Phe) (rs267608075)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074806 SCV000108017 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000200988 SCV000149312 likely benign not specified 2017-12-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115403 SCV000172809 likely benign Hereditary cancer-predisposing syndrome 2019-01-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV001080837 SCV000218996 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000200988 SCV000695841 likely benign not specified 2019-11-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3160A>T (p.Ile1054Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 246296 control chromosomes (gnomAD). The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant may be benign. c.3160A>T has been reported in the literature in individuals affected with Lynch Syndrome (Steinke_2008) and Hereditary Breast and Ovarian Cancer (Pal_2012, Grant_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000074806 SCV000837909 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586516 SCV000889484 likely benign not provided 2017-10-11 criteria provided, single submitter clinical testing
Color RCV000115403 SCV000910609 benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
Mendelics RCV000986730 SCV001135831 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586516 SCV001152298 likely benign not provided 2016-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986730 SCV001302730 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000586516 SCV000778622 likely benign not provided 2017-11-10 no assertion criteria provided clinical testing

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