VCV000042471.43 - ClinVar

NM_000179.3(MSH6):c.3438+14A>T

Germline

Top reviewed classifications are shown here.

Submission summary:

23 submissions

23 submitters

8 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.3438+14A>T

Variation ID: 42471 Accession: VCV000042471.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47803699 (GRCh38) [ NCBI UCSC ] 2: 48030838 (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	Mar 24, 2015	Sep 29, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3438+14A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001281492.2:c.3048+14A>T		intron variant
NM_001281493.2:c.2532+14A>T		intron variant
NM_001281494.2:c.2532+14A>T		intron variant
NC_000002.12:g.47803699A>T
NC_000002.11:g.48030838A>T
NG_007111.1:g.25553A>T
LRG_219:g.25553A>T
LRG_219t1:c.3438+14A>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:47803698:A:T

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.

0.40096 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.31462

The Genome Aggregation Database (gnomAD) 0.32279

Trans-Omics for Precision Medicine (TOPMed) 0.33685

1000 Genomes Project 0.40096

Exome Aggregation Consortium (ExAC) 0.40426

The Genome Aggregation Database (gnomAD), exomes 0.41175

Links

dbSNP: rs2020911 ClinGen: CA012858 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	9294	9615

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.
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV000035324.37
Lynch syndrome	Benign (1)	reviewed by expert panel	Sep 5, 2013	RCV000074853.14
Lynch syndrome 5	Benign (5)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000410944.18
Hereditary cancer-predisposing syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Mar 31, 2015	RCV000448622.12
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	Apr 22, 2021	RCV001798078.10
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV001811241.19
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV002054557.14
Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3	Benign (1)	criteria provided, single submitter	Aug 11, 2021	RCV002482955.8

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: SCV000108065.3 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 (Jul 22, 2011)	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: SCV000058972.5 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Comment: This variant is classified as benign based on its high frequency in the general population (rs2020911, MAF >3%). Number of individuals with the variant: 8
Benign (Apr 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002042050.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022
Benign (Aug 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002802225.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
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: SCV000302878.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 31, 2015)	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: SCV000537327.1 First in ClinVar: Mar 25, 2017 Last updated: Mar 25, 2017
Benign (Nov 19, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170361.11 First in ClinVar: Jun 23, 2014 Last updated: Aug 27, 2017	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 (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: SCV000744299.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (May 27, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110157.8 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: 30 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Benign (Dec 07, 2015)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487973.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
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: SCV004015978.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Jan 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV004233052.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: This variant is classified as Benign based on local population frequency. This variant was detected in 77% of patients studied by a panel of primary … (more) This variant is classified as Benign based on local population frequency. This variant was detected in 77% of patients studied by a panel of primary immunodeficiencies. Number of patients: 73. Only high quality variants are reported. (less) Number of individuals with the variant: 73 Age: <18 years Sex: mixed
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: SCV002442274.3 First in ClinVar: Apr 12, 2022 Last updated: Feb 14, 2024
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: SCV000604273.9 First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024
Benign (Aug 26, 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: SCV002615188.2 First in ClinVar: Nov 29, 2022 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)
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: SCV005243568.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jan 13, 2018)	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: SCV000430976.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257252.2 First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017
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: SCV000734219.1 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: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592640.2 First in ClinVar: Aug 27, 2017 Last updated: Jan 26, 2021	Number of individuals with the variant: 50
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: SCV001905842.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001925467.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001953463.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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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 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.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MSH6	-	-	-	-
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3438%2B14A%3ET	-	-	-	-

Text-mined citations for rs2020911 ...

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.3438+14A>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2020911 ...