NM_000179.3(MSH6):c.-8C>T AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: May 5, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000587581.34

Allele description

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

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

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

HGVS:

NC_000002.12:g.47783226C>T
NG_007111.1:g.5080C>T
NM_000179.3:c.-8C>TMANE SELECT
NM_001281492.2:c.-8C>T
NM_001281493.2:c.-744C>T
LRG_219t1:c.-8C>T
LRG_219:g.5080C>T
NC_000002.11:g.48010365C>T
NM_000179.2:c.-8C>T

Links:

dbSNP: rs565211544

NCBI 1000 Genomes Browser:

rs565211544

Molecular consequence:

NM_000179.3:c.-8C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281492.2:c.-8C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281493.2:c.-744C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211373	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jun 9, 2020)	germline	clinical testing	Citation Link,
SCV000601620	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 5, 2022)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26888055, 26467025
SCV000885719	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jan 28, 2018)	germline	clinical testing	Citation Link,
SCV001152284	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2019)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.

Liu Q, Thompson BA, Ward RL, Hesson LB, Sloane MA.

Hum Mutat. 2016 May;37(5):417-26. doi: 10.1002/humu.22971. Epub 2016 Mar 18. Review.

PubMed [citation]

PMID:: 26888055

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000211373.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 26888055)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601620.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885719.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001152284.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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