ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3246G>T (p.Pro1082=)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000179.3(MSH6):c.3246G>T (p.Pro1082=)
Variation ID: 42470 Accession: VCV000042470.73
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p16.3 2: 47803493 (GRCh38) [ NCBI UCSC ] 2: 48030632 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 20, 2015 May 12, 2024 Jun 13, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000179.3:c.3246G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Pro1082= synonymous NM_001281492.2:c.2856G>T NP_001268421.1:p.Pro952= synonymous NM_001281493.2:c.2340G>T NP_001268422.1:p.Pro780= synonymous NM_001281494.2:c.2340G>T NP_001268423.1:p.Pro780= synonymous NC_000002.12:g.47803493G>T NC_000002.11:g.48030632G>T NG_007111.1:g.25347G>T LRG_219:g.25347G>T LRG_219t1:c.3246G>T LRG_219p1:p.Pro1082= - Protein change
- Other names
- p.P1082P:CCG>CCT
- Canonical SPDI
- NC_000002.12:47803492:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00140 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00140
Trans-Omics for Precision Medicine (TOPMed) 0.00306
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00392
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9037 | 9343 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Benign/Likely benign (12) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000035323.38 | |
Benign (1) |
reviewed by expert panel
|
Jun 13, 2018 | RCV000074825.8 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 21, 2023 | RCV000126832.13 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2023 | RCV000614249.12 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000757474.32 | |
Benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV001080525.9 | |
Likely benign (1) |
criteria provided, single submitter
|
Mar 21, 2022 | RCV001798077.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Benign
(Jun 13, 2018)
|
reviewed by expert panel
Method: curation
|
Lynch syndrome 1
Affected status: yes
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108036.4
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability < 0.001 (0.00065)
|
|
Benign
(Nov 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000170360.11
First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
Benign
(Feb 22, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110154.8
First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Benign
(Jul 14, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002527991.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Benign
(Jun 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885716.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
|
|
Likely benign
(Aug 02, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058971.5
First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016 |
Comment:
Pro1082Pro in exon 5 of MSH6: This variant has been reported in individuals wit h hereditary breast and colorectal cancer, and hereditary breast cancer (3 … (more)
Pro1082Pro in exon 5 of MSH6: This variant has been reported in individuals wit h hereditary breast and colorectal cancer, and hereditary breast cancer (3 of 27 2 chromosomes, ~1%) and was absent from 332 control chromosomes (Wasielewski 201 0). It has also been reported in dbSNP with a frequency of about 1% (rs3136351) and as a polymorphism without frequency information in individuals with HNPCC, H NPCC-related tumors, and CRC (Wijnen 1999, Woods 2005, Kets 2006, Perez-Caborner o 2009). This variant is not expected to have clinical significance because it d oes not alter an amino acid residue and is not located near a splice junction. (less)
Number of individuals with the variant: 1
|
|
Benign
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070931.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
Benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552333.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
|
|
Likely benign
(Sep 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212729.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000302875.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
Benign
(Mar 31, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537401.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
|
|
Benign
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744296.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135835.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
Benign
(May 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001297509.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
|
|
Likely benign
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042047.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 11, 2023 |
|
|
Benign
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV004014933.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
|
|
Likely benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015999.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
Benign
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888267.4
First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024 |
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000252628.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001152301.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
MSH6: BP4, BP7, BS2
Number of individuals with the variant: 20
|
|
Benign
(-)
|
no assertion criteria provided
Method: research
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257246.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Number of individuals with the variant: 3
|
|
Likely benign
(May 13, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745653.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800479.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921820.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome 5
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734218.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Likely benign
(Nov 10, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000788048.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
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: SCV000592629.2 First in ClinVar: Oct 02, 2016 Last updated: May 03, 2018 |
Comment:
The MSH6 p.Pro1082Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not … (more)
The MSH6 p.Pro1082Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. This variant was identified in the literature in 5 of 1364 proband chromosomes (frequency: 0.004) from individuals with colorectal cancer or Lynch Syndrome-related tumours but was not identified in 170 control chromosomes from these studies (Kets 2006, Kolodner 1999, Pastrello 2011, Perez-Cabornero 2009, Woods 2005). The variant was also identified in the following databases: “InSiGHT Colon Cancer Database”, COSMIC, “MisMatch Repair Variants Database”, dbSNP (ID: rs3136351) “With probable-non-pathogenic allele”, and UMD (15X as a likely neutral variant). In UMD it was reported to co-occur with a pathogenic mutation in the MLH1 gene (MLH1 c.518T>G (p.Leu173Arg)), increasing the likelihood that the MSH6 p.Val1082Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 5 of 2500 chromosomes (frequency: 0.002), Exome Variant Server project in 46 of 8600 European American and in 5 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 424 of 122862 chromosomes (frequency: 0.003) from a population of European (Non-Finnish)/East Asian/Other/African/Latino/South Asian/European (Finnish) individuals, increasing the likelihood this could be a low frequency benign variant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. (less)
Number of individuals with the variant: 5
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957947.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977633.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
click to load more click to collapse |
Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry. | Okkels H | Applied immunohistochemistry & molecular morphology : AIMM | 2012 | PMID: 22495361 |
Integrated analysis of unclassified variants in mismatch repair genes. | Pastrello C | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21239990 |
Association of rare MSH6 variants with familial breast cancer. | Wasielewski M | Breast cancer research and treatment | 2010 | PMID: 19924528 |
A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR. | Perez-Cabornero L | European journal of cancer (Oxford, England : 1990) | 2009 | PMID: 19250818 |
Feasibility of screening for Lynch syndrome among patients with colorectal cancer. | Hampel H | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18809606 |
Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability. | Kets CM | British journal of cancer | 2006 | PMID: 17117178 |
High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes. | Woods MO | Clinical cancer research : an official journal of the American Association for Cancer Research | 2005 | PMID: 16203774 |
Germ-line msh6 mutations in colorectal cancer families. | Kolodner RD | Cancer research | 1999 | PMID: 10537275 |
Familial endometrial cancer in female carriers of MSH6 germline mutations. | Wijnen J | Nature genetics | 1999 | PMID: 10508506 |
Frameshift mutations of the hMSH6 gene in human leukemia cell lines. | Hosoya N | Japanese journal of cancer research : Gann | 1998 | PMID: 9510473 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH6 | - | - | - | - |
http://www.insight-database.org/classifications/?gene=MSH6&variant=c.3246G%3ET | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs3136351 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.