Submissions for variant NM_000179.3(MSH6):c.-8C>T

gnomAD frequency: 0.00003  dbSNP: rs565211544

Total submissions: 14

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	Lynch syndrome 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	2022-05-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0004 (12/30232 chromosomes in South Asian subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. To the best of our knowledge, the variant has not been reported in individuals with a MSH6 related disorder in the published literature. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212613	SCV000695933	benign	not specified	2021-09-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.-8C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00011 in 275432 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.-8C>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1) or VUS (n=5). Based on the evidence outlined above, the variant was classified as 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 Diagnostics, LLC DBA Color Health	RCV000131026	SCV000902749	likely benign	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587581	SCV001152284	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000412463	SCV004015207	uncertain significance	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing	This alteration results in substitution of nucleotide T for C in the 8 position upstream from codon one (5 prime untranslated region). This variant’s frequency is reported as T=0.00005 (6/115414, ExAC), T=0.000 (1/5008, 1000G), and T=0.0000 (1/30878, GnomAD). This variant is also reported in ClinVar as variant of unknown significance (10 reports). This variant is considered as variant of unknown significance.
Myriad Genetics, Inc.	RCV000412463	SCV004045689	likely benign	Lynch syndrome 5	2023-05-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003915036	SCV004733966	likely benign	MSH6-related condition	2020-03-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.