ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4002-10T>A (rs545466048)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081736 SCV000166235 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000590285 SCV000211331 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.4002-10T>A or IVS9-10T>A and consists of a T>A nucleotide substitution at the -10 position of intron 9 of the MSH6 gene. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging. This variant was observed in two unrelated individuals with early-onset colorectal cancer whose family histories did not fulfill Amsterdam II criteria, and in an individual with an MSI-high gastric cancer (Limburg 2011, Yamashita 2013). MSH6 c.4002-10T>A was observed at an allele frequency of 0.16% (15/9,010) in individuals of Ashnenazi Jewish ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MSH6 c.4002-10T>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000160702 SCV000539708 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD describes as VUS; ClinVar: 1LB; Unlikely to impact splicing
Genetic Services Laboratory,University of Chicago RCV000160702 SCV000595857 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160702 SCV000601600 uncertain significance not specified 2017-01-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160702 SCV000695909 benign not specified 2019-05-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.4002-10T>A alters a non-conserved nucleotide. 4/5 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 0.00026 in 244976 control chromosomes (gnomAD). The observed variant frequency is approximately 1.8 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. The variant, c.4002-10T>A, has been reported in the literature in colorectal, gastric or breast cancer patients without strong evidence for causality (Limburg_2011, Yamashita_2013, Bonache_2018). A co-occurrence with another pathogenic variant has been reported (MSH6 c.3477C>G, p.Tyr1159X; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS (n=5), Likely benign (n=1), Benign (n=1)) and one expert panel, InSiGHT, classified as uncertain significance before 2014. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000074975 SCV000837933 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000771079 SCV000902614 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000986753 SCV001135868 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590285 SCV001152304 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986753 SCV001300825 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-04-18 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.

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