ClinVar Miner

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

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Total submissions: 11
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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 The c.-8C>T variant is located in the 5' untranslated region (5’ UTR) of the MSH6 gene. This variant results from a C to T substitution 8 nucleotides upstream from the first translated codon. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 12,000 alleles tested) in our clinical cohort (includes this individual).This nucleotide position is well conserved in available vertebrate species.Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear.
GeneDx RCV000587581 SCV000211373 likely benign not provided 2020-06-09 criteria provided, single submitter clinical testing Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 26888055)
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc 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 Laboratories, Mayo Clinic RCV000212613 SCV000691914 uncertain significance not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354724 SCV001549408 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 c.-8C>T variant was not identified in literature nor the UMD-LSDB database. The variant was identified in dbSNP (ID: rs565211544) as "With other allele", ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, Quest Diagnostics, ARUP Laboratories, Mayo Clinic, Integrated Genetics, InSiGHT, University of Chicago; classified as benign by GeneDx). The variant was identified in control databases in 30 of 270614 chromosomes (1 homozygous) at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 34030 chromosomes (freq: 0.00009), European Non-Finnish in 11 of 122794 chromosomes (freq: 0.00009), European Finnish in 3 of 25752 chromosomes (freq: 0.0001), and South Asian in 13 of 30416 chromosomes (freq: 0.0004, increasing the likelihood this could be a low frequency benign variant), while the variant was not observed in the African, Other, Ashkenazi Jewish, or East Asian populations. This variant is located in the MSH6 promoter region, 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. The MSH6 promoter region has a high GC content and consensus binding sequences for a number of transcription factors (Szadkowski 2002), suggesting variants in this region could affect expression. This variant was identified by our laboratory in the homozygous state in a patient with MSH6-deficient endometrial cancer but who does not have Constitutional Mismatch Repair Deficiency syndrome; however, we cannot rule out the possibility that this variant may result in reduced expression. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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