VCV000090964.64 - ClinVar

NM_000251.3(MSH2):c.23C>T (p.Thr8Met)

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_000251.3(MSH2):c.23C>T (p.Thr8Met)

Variation ID: 90964 Accession: VCV000090964.64

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47403214 (GRCh38) [ NCBI UCSC ] 2: 47630353 (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	Jun 9, 2014	Oct 20, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000251.3:c.23C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000242.1:p.Thr8Met	missense
NM_001258281.1:c.-31+39C>T		intron variant
NC_000002.12:g.47403214C>T
NC_000002.11:g.47630353C>T
NG_007110.2:g.5091C>T
LRG_218:g.5091C>T
LRG_218t1:c.23C>T	LRG_218p1:p.Thr8Met
	P43246:p.Thr8Met

... more HGVS ... less HGVS

Protein change

T8M

Other names

p.T8M:ACG>ATG

Canonical SPDI

NC_000002.12:47403213:C: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.

0.00519 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

The Genome Aggregation Database (gnomAD) 0.00184

Trans-Omics for Precision Medicine (TOPMed) 0.00252

The Genome Aggregation Database (gnomAD), exomes 0.00303

Exome Aggregation Consortium (ExAC) 0.00360

1000 Genomes Project 30x 0.00484

1000 Genomes Project 0.00519

Links

ClinGen: CA020551 UniProtKB: P43246#VAR_013171 dbSNP: rs17217716 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.
MSH2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7402	7564

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 (1)	reviewed by expert panel	Sep 5, 2013	RCV000076466.11
not specified	Benign (9)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000121556.30
Lynch syndrome 1	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	May 28, 2019	RCV000144624.10
Hereditary cancer-predisposing syndrome	Benign (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2023	RCV000130682.13
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000434381.24
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001082308.10
Carcinoma of colon	Likely benign (1)	no assertion criteria provided	-	RCV001353559.3
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	Dec 13, 2021	RCV003149750.4
Lynch syndrome 1 Mismatch repair cancer syndrome 2 Muir-Torré syndrome	Likely benign (1)	criteria provided, single submitter	May 21, 2022	RCV002498369.3

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: SCV000107495.3 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): Multifactorial likelihood analysis posterior probability <0.001 Converted during submission to Benign.
Benign (Feb 09, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511017.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Uncertain significance (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781766.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Benign (Jun 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806029.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135688.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Benign (Sep 21, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001156593.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020
Benign (Oct 09, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534471.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Nov 15, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170341.13 First in ClinVar: Jun 09, 2014 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 30333958, 21681552, 22290698, 25371881, 23760103, 24728327, 10777691, 26332594, 21615986, 15340835, 15849733, 16810763, 18383312, 26951660, 28580595, 30998989, … (more) This variant is associated with the following publications: (PMID: 30333958, 21681552, 22290698, 25371881, 23760103, 24728327, 10777691, 26332594, 21615986, 15340835, 15849733, 16810763, 18383312, 26951660, 28580595, 30998989, 31237724) (less)
Benign (Dec 13, 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: SCV003838293.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552182.4 First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 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: SCV000166272.13 First in ClinVar: Jun 23, 2014 Last updated: Feb 14, 2024
Benign (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002544031.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: MSH2: BS1, BS2 Number of individuals with the variant: 2
Likely benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000430908.3 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Mar 05, 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: SCV000685038.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Likely benign (May 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Muir-Torré syndrome Mismatch repair cancer syndrome 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807667.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Aug 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV004228015.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024
Benign (Sep 03, 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: SCV000185569.9 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)
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: SCV005241318.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Lynch syndrome I Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189951.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Likely benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691894.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809338.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 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: SCV001953189.1 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970363.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (Nov 17, 2022)	no assertion criteria provided Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV003839735.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023
Likely benign (Mar 02, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000788032.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Likely 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: SCV000592449.2 First in ClinVar: Jun 09, 2014 Last updated: Apr 13, 2021	Comment: The p.Thr8Met variant has been identified in 7/4128 proband chromsomes in individuals with Lynch syndrome, and was also identified in 2/200 control chromosomes (Ali 2012, … (more) The p.Thr8Met variant has been identified in 7/4128 proband chromsomes in individuals with Lynch syndrome, and was also identified in 2/200 control chromosomes (Ali 2012, Chao 2008, Mangold 2005, Nomura 2000, Valentin 2011, Wang 2006, Wei 2011), increasing the likelihood that this is a benign variant. The variant has also been reported in the HGMD, LOVD and several colon cancer databases, some of which suggest that it is probably neutral. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs17217716) with a MAF score of 0.008 (1000 Genomes) and it is observed at low frequency in the Han Chinese and Japanese HapMap population samples, increasing the likelihood this variant may be a common low frequency variant with no clinical significance. The p.Thr8 residue is conserved across mammals but computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign. (less) Number of individuals with the variant: 1
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085750.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this 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:

The p.Thr8Met variant has been identified in 7/4128 proband chromsomes in individuals with Lynch syndrome, and was also identified in 2/200 control chromosomes (Ali 2012, Chao 2008, Mangold 2005, Nomura 2000, Valentin 2011, Wang 2006, Wei 2011), increasing the likelihood that this is a benign variant. The variant has also been reported in the HGMD, LOVD and several colon cancer databases, some of which suggest that it is probably neutral. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs17217716) with a MAF score of 0.008 (1000 Genomes) and it is observed at low frequency in the Han Chinese and Japanese HapMap population samples, increasing the likelihood this variant may be a common low frequency variant with no clinical significance. The p.Thr8 residue is conserved across mammals but computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted 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
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
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.23C%3ET	-	-	-	-

Text-mined citations for rs17217716 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000251.3(MSH2):c.23C>T (p.Thr8Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs17217716 ...