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NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(7)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Sep 25, 2021)
Last evaluated:
Oct 12, 2020
Accession:
VCV000127563.12
Variation ID:
127563
Description:
single nucleotide variant
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NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu)

Allele ID
133020
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2p16.3
Genomic location
2: 47799729 (GRCh38) GRCh38 UCSC
2: 48026868 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_219:g.21583T>G
LRG_219t1:c.1746T>G LRG_219p1:p.Phe582Leu
NC_000002.11:g.48026868T>G
... more HGVS
Protein change
F582L, F280L, F452L
Other names
p.F582L:TTT>TTG
Canonical SPDI
NC_000002.12:47799728:T:G
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (G)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00002
Links
ClinGen: CA009115
dbSNP: rs201518545
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 3 criteria provided, multiple submitters, no conflicts Sep 2, 2020 RCV000235184.5
Uncertain significance 1 criteria provided, single submitter Oct 12, 2020 RCV000230963.8
Uncertain significance 1 criteria provided, single submitter Dec 4, 2015 RCV000409045.1
Uncertain significance 1 criteria provided, single submitter Jan 7, 2019 RCV001192457.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations May 11, 2020 RCV000115382.9
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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
5678 5712

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(May 11, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000216925.5
Submitted: (Nov 30, 2020)
Evidence details
Comment:
The p.F582L variant (also known as c.1746T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide … (more)
Uncertain significance
(Feb 13, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000149291.14
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; … (more)
Uncertain significance
(Dec 04, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 5
Allele origin: unknown
Counsyl
Accession: SCV000487946.1
Submitted: (Nov 23, 2016)
Evidence details
Likely benign
(Sep 20, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000903501.1
Submitted: (Nov 06, 2018)
Evidence details
Uncertain significance
(Jan 07, 2019)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360593.1
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (1)
Comment:
Variant summary: MSH6 c.1746T>G (p.Phe582Leu) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Two of … (more)
Uncertain significance
(Sep 02, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: unknown
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469815.1
Submitted: (Dec 31, 2020)
Evidence details
Uncertain significance
(Oct 12, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000283726.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
This sequence change replaces phenylalanine with leucine at codon 582 of the MSH6 protein (p.Phe582Leu). The phenylalanine residue is moderately conserved and there is a … (more)
Uncertain significance
(Jun 07, 2019)
criteria provided, single submitter
Method: clinical testing
Not provided
Allele origin: germline
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713985.1
Submitted: (May 26, 2021)
Evidence details

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
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 rs201518545...

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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 Oct 30, 2021