NM_000179.3(MSH6):c.3173-1G>C AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000201971.18

Allele description [Variation Report for NM_000179.3(MSH6):c.3173-1G>C]

NM_000179.3(MSH6):c.3173-1G>C

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.3173-1G>C

HGVS:

NC_000002.12:g.47803419G>C
NG_007111.1:g.25273G>C
NM_000179.3:c.3173-1G>CMANE SELECT
NM_001281492.2:c.2783-1G>C
NM_001281493.2:c.2267-1G>C
NM_001281494.2:c.2267-1G>C
NM_001406795.1:c.3269-1G>C
NM_001406796.1:c.3173-1G>C
NM_001406797.1:c.2876-1G>C
NM_001406798.1:c.3173-175G>C
NM_001406799.1:c.2648-1G>C
NM_001406800.1:c.3173-1G>C
NM_001406801.1:c.2876-1G>C
NM_001406802.1:c.3269-1G>C
NM_001406803.1:c.2309-1G>C
NM_001406804.1:c.3095-1G>C
NM_001406805.1:c.2876-1G>C
NM_001406806.1:c.2648-1G>C
NM_001406807.1:c.2648-1G>C
NM_001406808.1:c.3173-1G>C
NM_001406809.1:c.3173-1G>C
NM_001406811.1:c.2267-1G>C
NM_001406812.1:c.2267-1G>C
NM_001406813.1:c.3179-1G>C
NM_001406814.1:c.2267-1G>C
NM_001406815.1:c.2267-1G>C
NM_001406816.1:c.2267-1G>C
NM_001406817.1:c.1607-1G>C
NM_001406818.1:c.2876-1G>C
NM_001406819.1:c.2876-1G>C
NM_001406820.1:c.2876-1G>C
NM_001406821.1:c.2876-1G>C
NM_001406822.1:c.2876-1G>C
NM_001406823.1:c.2267-1G>C
NM_001406824.1:c.2876-1G>C
NM_001406825.1:c.2876-1G>C
NM_001406826.1:c.3005-1G>C
NM_001406827.1:c.2876-1G>C
NM_001406828.1:c.2876-1G>C
NM_001406829.1:c.2267-1G>C
NM_001406830.1:c.2876-1G>C
NM_001406831.1:c.-47-1G>C
NM_001406832.1:c.20-1G>C
NM_001407362.1:c.1118-1G>C
LRG_219t1:c.3173-1G>C
LRG_219:g.25273G>C
NC_000002.11:g.48030558G>C
NM_000179.2:c.3173-1G>C
c.3173-1G>C

Links:

dbSNP: rs397515875

NCBI 1000 Genomes Browser:

rs397515875

Molecular consequence:

NM_001406798.1:c.3173-175G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000179.3:c.3173-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001281492.2:c.2783-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001281493.2:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001281494.2:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406795.1:c.3269-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406796.1:c.3173-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406797.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406799.1:c.2648-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406800.1:c.3173-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406801.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406802.1:c.3269-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406803.1:c.2309-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406804.1:c.3095-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406805.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406806.1:c.2648-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406807.1:c.2648-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406808.1:c.3173-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406809.1:c.3173-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406811.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406812.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406813.1:c.3179-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406814.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406815.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406816.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406817.1:c.1607-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406818.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406819.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406820.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406821.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406822.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406823.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406824.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406825.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406826.1:c.3005-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406827.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406828.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406829.1:c.2267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406830.1:c.2876-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406831.1:c.-47-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406832.1:c.20-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407362.1:c.1118-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000257238	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Likely pathogenic	unknown	research
SCV002047771	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Mar 15, 2021)	germline	clinical testing	Citation Link,
SCV004221210	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 1, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000257238

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Likely pathogenic

unknown

research

SCV002047771

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(Mar 15, 2021)

germline

clinical testing

Citation Link,

SCV004221210

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Dec 1, 2022)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Mayo Clinic Laboratories, Mayo Clinic, SCV000257238.1

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

#	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		1	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002047771.1

#	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.3173-1G>C variant (rs397515875), to our knowledge, is not reported in the medical literature but is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 42469). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 4, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004221210.1

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

Description

This variant disrupts a canonical splice-acceptor site and interferes with normal MSH6 mRNA splicing. The variant has not been reported in individuals with MSH6-related diseases in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

#	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

Last Updated: Apr 20, 2024

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