VCV000036581.47 - ClinVar

NM_000179.3(MSH6):c.116G>A (p.Gly39Glu)

Germline

Top reviewed classifications are shown here.

Submission summary:

27 submissions

27 submitters

9 conditions

Reviewed by expert panel

No known pathogenicity

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000179.3(MSH6):c.116G>A (p.Gly39Glu)

Variation ID: 36581 Accession: VCV000036581.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47783349 (GRCh38) [ NCBI UCSC ] 2: 48010488 (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	Apr 12, 2013	Sep 29, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.116G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Gly39Glu	missense
NM_001281492.2:c.116G>A	NP_001268421.1:p.Gly39Glu	missense
NM_001281493.2:c.-621G>A		5 prime UTR
NC_000002.12:g.47783349G>A
NC_000002.11:g.48010488G>A
NG_007111.1:g.5203G>A
LRG_219:g.5203G>A
LRG_219t1:c.116G>A	LRG_219p1:p.Gly39Glu
	P52701:p.Gly39Glu

... more HGVS ... less HGVS

Protein change

G39E

Other names

Canonical SPDI

NC_000002.12:47783348:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.20088 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.20088

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.17965

The Genome Aggregation Database (gnomAD) 0.18742

Trans-Omics for Precision Medicine (TOPMed) 0.18945

1000 Genomes Project 30x 0.19628

Links

ClinGen: CA008209 UniProtKB: P52701#VAR_004490 dbSNP: rs1042821 VarSome

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
Gene	OMIM	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	9164	9483

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.
Lynch syndrome	Benign (3)	reviewed by expert panel	Sep 5, 2013	RCV000030258.16
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV000034489.27
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Feb 29, 2016	RCV000035318.37
Lynch syndrome 1	Benign (2)	criteria provided, single submitter	Aug 18, 2017	RCV000144626.10
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Dec 11, 2019	RCV000132091.14
Lynch syndrome 5	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000609254.16
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001079921.14
Carcinoma of colon	Benign (1)	no assertion criteria provided	-	RCV001353505.9
Breast carcinoma	Benign (1)	criteria provided, single submitter	Jan 1, 2019	RCV001262327.9

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.
no known pathogenicity (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000107840.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comments (2): MAF >1% Converted during submission to Benign.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302867.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001892538.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 24622885, 29442465, 28932927, 27153395, 18523027, 19582761, 24689082, 22949387, 19685280, 22703879)
Benign (Dec 11, 2019)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535607.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Feb 29, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110149.8 First in ClinVar: Jan 17, 2014 Last updated: Aug 27, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH6 Number of individuals with the variant: 22 Sex: mixed
Benign (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast carcinoma Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440150.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015980.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000624619.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005243543.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Nov 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292086.1 First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016
Benign (Aug 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: no Allele origin: germline	IntelligeneCG Accession: SCV000611715.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Benign (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) 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: SCV000744284.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Oct 29, 2008)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058966.5 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Publications: PubMed (8) PubMed: 16270383‚ 8838326‚ 10537275‚ 10699937‚ 16203774‚ 15805151‚ 16771955‚ 18355840 Comment: Gly39Glu in exon 1 of MSH6: This variant is not expected to have clinical signif icance because it has been identified in 17% (1336/7748) of … (more) Gly39Glu in exon 1 of MSH6: This variant is not expected to have clinical signif icance because it has been identified in 17% (1336/7748) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs1042821). Gly39Glu in exon 1 of MSH6 (rs1042821; a llele frequency = 17%, 1336/7748) ** (less) Number of individuals with the variant: 6
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135774.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000430945.3 First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604270.10 First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004827941.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 35530
Benign (Oct 27, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187155.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
no known pathogenicity (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043349.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Benign. Number of individuals with the variant: 118 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Benign (Dec 02, 2011)	no assertion criteria provided Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052925.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015
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: SCV000734206.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Lynch syndrome I Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189953.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (3) PubMed: 22949387‚ 22703879‚ 18523027 Other databases https://51b5adfeab56f211e45ac7c7… https://51b5adfeab56f211e45ac7c77a44963c57db9fc5.googledrive.com/host/0B8HVsr5izQxJUi1XTzEtWFlRc00/index.html?gene=MSH6&protein=&variant=c.116G%3EA
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257208.2 First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017
Benign (-)	no assertion criteria provided Method: clinical testing	Carcinoma of colon 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: SCV000592563.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Gly39Glu variant has been previously reported in the literature and is recorded in dbSNP as a polymorphism with an average heterozygosity of 0.307+/-0.243 (dbSNP#: … (more) The p.Gly39Glu variant has been previously reported in the literature and is recorded in dbSNP as a polymorphism with an average heterozygosity of 0.307+/-0.243 (dbSNP#: rs1042821); this appreciable frequency in different populations of origin increases the likelihood this is a benign variant. In addition, this variant has been identified by our laboratory in at least one individual with a second pathogenic vairiant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant is classified as benign. (less)
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: SCV001906443.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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: SCV001921533.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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: SCV001959944.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
click to load more click to collapse

Comment:

Gly39Glu in exon 1 of MSH6: This variant is not expected to have clinical signif icance because it has been identified in 17% (1336/7748) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs1042821). Gly39Glu in exon 1 of MSH6 (rs1042821; a llele frequency = 17%, 1336/7748) **

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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as 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.

Comment:

The p.Gly39Glu variant has been previously reported in the literature and is recorded in dbSNP as a polymorphism with an average heterozygosity of 0.307+/-0.243 (dbSNP#: rs1042821); this appreciable frequency in different populations of origin increases the likelihood this is a benign variant. In addition, this variant has been identified by our laboratory in at least one individual with a second pathogenic vairiant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant is classified as benign.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.	Thompson BA	Human mutation	2013	PMID: 22949387
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors.	Campbell PT	Gut	2009	PMID: 18523027
Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer.	Hirata H	The Journal of urology	2008	PMID: 18355840
Mismatch repair polymorphisms and colorectal polyps: hMLH1-93G>A variant modifies risk associated with smoking.	Yu JH	The American journal of gastroenterology	2006	PMID: 16771955
Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain.	Sánchez de Abajo A	World journal of gastroenterology	2005	PMID: 16270383
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
No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer.	Vahteristo P	Journal of medical genetics	2005	PMID: 15805151
Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer.	Plaschke J	International journal of cancer	2000	PMID: 10699937
Germ-line msh6 mutations in colorectal cancer families.	Kolodner RD	Cancer research	1999	PMID: 10537275
Molecular cloning of the N-terminus of GTBP.	Nicolaides NC	Genomics	1996	PMID: 8838326
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH6	-	-	-	-
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.116G%3EA	-	-	-	-
https://51b5adfeab56f211e45ac7c77a44963c57db9fc5.googledrive.com/host/0B8HVsr5izQxJUi1XTzEtWFlRc00/index.html?gene=MSH6&protein=&variant=c.116G%3EA	-	-	-	-
click to load more click to collapse

Text-mined citations for rs1042821 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.116G>A (p.Gly39Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1042821 ...