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NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Jan 7, 2021)
Last evaluated:
Sep 24, 2020
Accession:
VCV000089257.7
Variation ID:
89257
Description:
single nucleotide variant
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NM_000179.2(MSH6):c.2175C>G (p.Ile725Met)

Allele ID
94731
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p16.3
Genomic location
2: 47800158 (GRCh38) GRCh38 UCSC
2: 48027297 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000002.11:g.48027297C>G
NC_000002.12:g.47800158C>G
NM_000179.2:c.2175C>G NP_000170.1:p.Ile725Met missense
... more HGVS
Protein change
I725M, I595M, I423M
Other names
-
Canonical SPDI
NC_000002.12:47800157:C:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Links
ClinGen: CA009807
UniProtKB: P52701#VAR_043955
dbSNP: rs63750304
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Jun 29, 2016 RCV000410569.1
Uncertain significance 1 criteria provided, single submitter Sep 24, 2020 RCV000556059.4
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Mar 22, 2017 RCV000565677.2
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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
5633 5667

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jun 29, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 5
Allele origin: unknown
Counsyl
Accession: SCV000488837.1
Submitted: (Nov 23, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Sep 24, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000624731.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces isoleucine with methionine at codon 725 of the MSH6 protein (p.Ile725Met). The isoleucine residue is weakly conserved and there is a … (more)
Likely benign
(Feb 22, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000908260.1
Submitted: (Nov 06, 2018)
Evidence details
Uncertain significance
(Mar 22, 2017)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000662560.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The p.I725M variant (also known as c.2175C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide … (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
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
Classification of mismatch repair gene missense variants with PON-MMR. Ali H Human mutation 2012 PMID: 22290698
BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Domingo E Oncogene 2005 PMID: 15782118
Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Berends MJ American journal of human genetics 2002 PMID: 11709755

Text-mined citations for rs63750304...

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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 Mar 22, 2021