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NM_000179.3(MSH6):c.1822A>G (p.Ile608Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(5)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Jun 11, 2021)
Last evaluated:
Oct 21, 2020
Accession:
VCV000182626.11
Variation ID:
182626
Description:
single nucleotide variant
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NM_000179.3(MSH6):c.1822A>G (p.Ile608Val)

Allele ID
180063
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p16.3
Genomic location
2: 47799805 (GRCh38) GRCh38 UCSC
2: 48026944 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_219:g.21659A>G
LRG_219t1:c.1822A>G LRG_219p1:p.Ile608Val
NC_000002.11:g.48026944A>G
... more HGVS
Protein change
I608V, I306V, I478V
Other names
p.I608V:ATT>GTT
Canonical SPDI
NC_000002.12:47799804:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Links
ClinGen: CA009270
dbSNP: rs201613780
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Aug 4, 2020 RCV000491442.6
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Aug 21, 2017 RCV000589796.1
Uncertain significance 1 criteria provided, single submitter Oct 21, 2020 RCV000196510.9
Likely benign 2 criteria provided, single submitter Apr 30, 2018 RCV000757926.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MSH6 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
5681 5715

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jul 01, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695797.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (2)
Comment:
Variant summary: The MSH6 c.1822A>G (p.Ile608Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant, … (more)
Likely benign
(Apr 30, 2018)
criteria provided, single submitter
Method: research
Lynch syndrome
(Autosomal dominant inheritance)
Allele origin: germline
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000886444.1
Submitted: (Nov 05, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The MSH6 variant designated as NM_000179.2:c.1822A>G (p.Ile608Val) is classified as likely benign. Based on in-silico scores the variant has a prior probability of pathogenicity of … (more)
Uncertain significance
(Aug 21, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000211282.14
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This variant is denoted MSH6 c.1822A>G at the cDNA level, p.Ile608Val (I608V) at the protein level, and results in the change of an Isoleucine to … (more)
Uncertain significance
(Mar 10, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000580260.4
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (1)
Comment:
The p.I608V variant (also known as c.1822A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide … (more)
Uncertain significance
(Oct 21, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000254283.9
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces isoleucine with valine at codon 608 of the MSH6 protein (p.Ile608Val). The isoleucine residue is moderately conserved and there is a … (more)
Uncertain significance
(Aug 04, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000911114.3
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant replaces isoleucine with valine at codon 608 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
Uncertain significance
(-)
no assertion criteria provided
Method: clinical testing
Lynch syndrome
Allele origin: unknown
Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550941.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The MSH6 p.Ile608Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome-related cancer and/or colorectal polyps … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Tsai GJ Genetics in medicine : official journal of the American College of Medical Genetics 2019 PMID: 30374176
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Yurgelun MB Gastroenterology 2015 PMID: 25980754
CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. Terui H Journal of biomedical science 2013 PMID: 23621914

Text-mined citations for rs201613780...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021