ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2146A>G (p.Thr716Ala)

dbSNP: rs749711246
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550483 SCV000624729 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572538 SCV000669937 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-14 criteria provided, single submitter clinical testing The p.T716A variant (also known as c.2146A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2146. The threonine at codon 716 is replaced by alanine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000572538 SCV000906821 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
GeneDx RCV001548306 SCV001768193 uncertain significance not provided 2021-12-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25980754, 22949379, 17531815, 21120944)
Sema4, Sema4 RCV000572538 SCV002535702 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-10 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001548306 SCV004221169 uncertain significance not provided 2023-07-13 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in one individual with colon cancer from The Cancer Genome Atlas dataset (PMID: 29684080 (2018)) and another individual with T-cell acute lymphoblastic leukemia (PMID: 31721781 (2019)). The frequency of this variant in the general population, 0.000004 (1/250930 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health RCV004003671 SCV004836029 uncertain significance Lynch syndrome 2023-12-01 criteria provided, single submitter clinical testing

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