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NM_000179.3(MSH6):c.905G>A (p.Arg302Lys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Sep 25, 2021)
Last evaluated:
Sep 15, 2020
Accession:
VCV000216324.11
Variation ID:
216324
Description:
single nucleotide variant
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NM_000179.3(MSH6):c.905G>A (p.Arg302Lys)

Allele ID
212225
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p16.3
Genomic location
2: 47798888 (GRCh38) GRCh38 UCSC
2: 48026027 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000002.12:g.47798888G>A
NG_007111.1:g.20742G>A
NM_000179.3:c.905G>A MANE Select NP_000170.1:p.Arg302Lys missense
... more HGVS
Protein change
R302K, R172K
Other names
-
Canonical SPDI
NC_000002.12:47798887:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Links
ClinGen: CA073568
dbSNP: rs587781510
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 Sep 15, 2020 RCV000195580.7
Uncertain significance 1 criteria provided, single submitter May 15, 2019 RCV000521245.3
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jul 16, 2020 RCV000219538.3
not provided 1 no assertion provided - RCV000845040.1

Clinical features observed in individuals with this variant

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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
Likely benign
(Nov 01, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000273276.5
Submitted: (Nov 30, 2020)
Evidence details
Comment:
In silico models in agreement (benign)
Uncertain significance
(Sep 15, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000254337.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
This sequence change replaces arginine with lysine at codon 302 of the MSH6 protein (p.Arg302Lys). The arginine residue is highly conserved and there is a … (more)
Uncertain significance
(Jul 16, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV001353864.2
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant replaces arginine with lysine at codon 302 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
Uncertain significance
(May 15, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000616788.3
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
not provided
(-)
no assertion provided
Method: phenotyping only
Hereditary nonpolyposis colorectal cancer type 5
Turcot syndrome
Allele origin: unknown
GenomeConnect, ClinGen
Accession: SCV000986877.1
Submitted: (Jan 30, 2019)
Evidence details
Comment:
Variant interpretted as Uncertain significance and reported on 11/07/2016 by GTR ID Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (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
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
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. Grandval P Database : the journal of biological databases and curation 2013 PMID: 23729658

Text-mined citations for rs587781510...

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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 Dec 04, 2021