ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.-8C>T (rs565211544)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131026 SCV000185956 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212613 SCV000211373 benign not specified 2014-08-29 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.
Counsyl RCV000412463 SCV000488847 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-07-05 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212613 SCV000595839 uncertain significance not specified 2016-02-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587581 SCV000601620 uncertain significance not provided 2019-02-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587581 SCV000695933 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.-8C>T is located in the 5' untranslated region causes an alteration of a non-conserved nucleotide. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 6/115414 (1/19234), predominantly in the South Asian cohort, 4/16244 (1/4061), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of South Asian origin. In addition, a large, broad control population database, gnomAD, that contains ExAC data and additional whole genome sequences, observed the variant with an allele frequency of 29/245886, predomanintly in the South Asian cohort, 13/30538 including 1 homozygote, however, this observation needs to be cautiously considered due to the database currently being in "early beta mode." The variant of interest has not, to our knowledge, been reported in affected individuals via publications, although multiple clinical diagnostic laboratories/databases classify the variant as "uncertain significance." Therefore, until additional information becomes available (clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000587581 SCV000885719 uncertain significance not provided 2018-01-28 criteria provided, single submitter clinical testing The MSH6 c.-8C>T variant (rs565211544) is not published in the medical literature, to our knowledge, but is listed as a variant of uncertain significance by several sources in the ClinVar database (Variation ID: 89164). The variant is listed in the Genome Aggregation Database in 30 out of 270614 alleles. This variant occurs 8 nucleotides before the translational start, the nucleotide at this position is not perfectly conserved across species, and the consequence of this substitution cannot be predicted with certainty. Studies of the transcriptional regulation of this region indicate this nucleotide may be involved in the regulation of this gene (Gazzoli 2003, Szadkowski 2002). Additionally, a translational prediction algorithm (NetStart 1.0) predicts this variant may alter translation. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Gazzoli I and Kolodner R. Regulation of the human MSH6 gene by the Sp1 transcription factor and alteration of promoter activity and expression by polymorphisms. Mol Cell Biol. 2003 Nov;23(22):7992-8007. Szadkowski M and Jiricny J. Identification and functional characterization of the promoter region of the human MSH6 gene. Genes Chromosomes Cancer. 2002 Jan;33(1):36-46.
Color RCV000131026 SCV000902749 likely benign Hereditary cancer-predisposing syndrome 2016-06-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587581 SCV001152284 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212613 SCV000691914 uncertain significance not specified no assertion criteria provided clinical testing

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