VCV000090903.50 - ClinVar

NM_000251.3(MSH2):c.2131C>T (p.Arg711Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

25 submissions

25 submitters

8 conditions

Reviewed by expert panel

Pathogenic

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.2131C>T (p.Arg711Ter)

Variation ID: 90903 Accession: VCV000090903.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 47476492 (GRCh38) [ NCBI UCSC ] 2: 47703631 (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_000251.3:c.2131C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000242.1:p.Arg711Ter	nonsense
NM_001258281.1:c.1933C>T	NP_001245210.1:p.Arg645Ter	nonsense
NC_000002.12:g.47476492C>T
NC_000002.11:g.47703631C>T
NG_007110.2:g.78369C>T
LRG_218:g.78369C>T
LRG_218t1:c.2131C>T	LRG_218p1:p.Arg711Ter

... more HGVS ... less HGVS

Protein change

R711*, R645*

Other names

Canonical SPDI

NC_000002.12:47476491: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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA020107 dbSNP: rs63750636 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	7404	7566

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	Pathogenic (5)	reviewed by expert panel	Sep 5, 2013	RCV000076405.12
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 29, 2023	RCV000129341.13
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Sep 13, 2024	RCV000202062.20
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 12, 2024	RCV000524377.10
Lynch syndrome 1 Mismatch repair cancer syndrome 1 Muir-Torré syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763494.2
not specified	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2019	RCV001000186.8
Lynch-like syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 2019	RCV001249926.1
Lynch syndrome 1	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Mar 25, 2024	RCV002272055.10

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.
Pathogenic (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: SCV000107434.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation introducing premature termination codon
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000837849.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017563.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 23, 2021)	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: SCV000184105.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (23) PubMed: 12362047‚ 12624141‚ 15235030‚ 15655560‚ 15849733‚ 17312306‚ 17569143‚ 18289827‚ 19419416‚ 24474082‚ 26437257‚ 27863258‚ 28874130‚ 28944238‚ 29025352‚ 29575718‚ 30274973‚ 30521064‚ 31162827‚ 31615790‚ 32338768‚ 32522261‚ 33422027 Comment: The p.R711* pathogenic mutation (also known as c.2131C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at … (more) The p.R711* pathogenic mutation (also known as c.2131C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2131. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in the germline of multiple patients with HNPCC/Lynch syndrome-associated malignancies and several of these individuals had tumors exhibiting a loss of MSH2 on immunohistochemistry (IHC) and/or microsatellite instability (Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Tang R et al. Clin Genet, 2009 Apr;75:334-45; Tanyi M et al. Eur J Surg Oncol, 2008 Dec;34:1322-7; Rios CA et al. Sao Paulo Med J, 2014;132:61-4; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Nowak JA et al. J Mol Diagn, 2017 01;19:84-91; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Ponz de Leon M et al. Scand J Gastroenterol, 2018 Jan;53:31-37; Schneider NB et al. Cancer Med, 2018 05;7:2078-2088; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781; Velázquez C et al. J Transl Med, 2020 06;18:232; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Xu Y et al. BMC Cancer, 2021 Jan;21:45). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196933.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 10, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary nonpolyposis colon cancer Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696236.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (6) PubMed: 24474082‚ 12362047‚ 17569143‚ 15655560‚ 15849733‚ 19419416 Comment: Variant summary: The MSH2 c.2131C>T (p.Arg711X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense … (more) Variant summary: The MSH2 c.2131C>T (p.Arg711X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.2152C>T(p.Gln718X), c.2633_2634delA(p.Glu878fsX3), etc.). This variant is absent in 121400 control chromosomes from ExAC. In literature and clinical databases, this variant is reported as a pathogenic variant and is found in several HNPCC families/patients, including one patient with Muir-Torre Syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Muir-Torré syndrome Mismatch repair cancer syndrome 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894280.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jan 30, 2019)	criteria provided, single submitter (Carneiro da Silva F et al. (PLoS One 2015)) Method: research	Lynch syndrome Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000914304.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Number of individuals with the variant: 1 Geographic origin: Brazil
Pathogenic (Apr 30, 2019)	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: SCV001156679.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The MSH2 c.2131C>T; p.Arg711Ter variant (rs63750636) is reported in several individuals with Lynch syndrome and an individual with Muir-Torre syndrome (Rios 2014, Rossi 2017, Schneider … (more) The MSH2 c.2131C>T; p.Arg711Ter variant (rs63750636) is reported in several individuals with Lynch syndrome and an individual with Muir-Torre syndrome (Rios 2014, Rossi 2017, Schneider 2018, see LOVD InSiGHT link). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 90903). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to InSiGHT database: https://databases.lovd.nl/shared/variants/MSH2#object_id=VariantOnTranscript%2CVariantOnGenome&id=MSH2&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00013950&search_VariantOnTranscript/DNA=c.2131C%3ET&page_size=100&page=1 Rios CA et al. Muir-Torre syndrome: case report and molecular characterization. Sao Paulo Med J. 2014;132(1):61-4. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Schneider NB et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Med. 2018 May;7(5):2078-2088. (less)
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821737.2 First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020	Comment: This is a point mutation replacing one nucleotide in the position 2131 of the MSH2 gene, leading in the replacement of Arginine with a termination … (more) This is a point mutation replacing one nucleotide in the position 2131 of the MSH2 gene, leading in the replacement of Arginine with a termination stop codon in the position 711 of the MSH2 protein. This particular variant has been described in international literature in families with Lynch syndrome and with Muir-Torre syndrome (PMID: 17569143, PMID: 17473388, PMID: 16451135, PMID: 15235030). The mutation database ClinVar contains an entry for this variant (Variation ID: 90903). (less)
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601456.2 First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2021	Publications: PubMed (13) PubMed: 12132870‚ 18289827‚ 17473388‚ 21868491‚ 21387278‚ 29575718‚ 30521064‚ 30274973‚ 28874130‚ 24474082‚ 17312306‚ 15235030‚ 12362047 Comment: The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more) The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
Pathogenic (Jul 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579365.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM2_SUP, PP1, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (Oct 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758565.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Pathogenic (Jan 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556617.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Comment: PVS1, PS4, PP5.
Pathogenic (Aug 07, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004188002.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Mar 29, 2023)	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: SCV000685015.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 15235030‚ 15849733‚ 16451135‚ 17312306‚ 17569143‚ 18289827‚ 19419416‚ 21868491‚ 24474082‚ 28874130‚ 29575718‚ 30274973‚ 30521064 Comment: This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 12, 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: SCV000253805.10 First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 28492532‚ 15849733‚ 24362816‚ 12132870‚ 12362047‚ 15235030‚ 16451135‚ 17473388‚ 17569143‚ 18289827 Comment: This sequence change creates a premature translational stop signal (p.Arg711) in the MSH2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg711) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63750636, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and/or non-polyposis colorectal cancer (PMID: 12132870, 12362047, 15235030, 15849733, 16451135, 17473388, 17569143, 18289827). ClinVar contains an entry for this variant (Variation ID: 90903). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lynch syndrome 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805308.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Jan 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: SCV004825658.1 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)	Publications: PubMed (13) PubMed: 15235030‚ 15849733‚ 16451135‚ 17312306‚ 17569143‚ 18289827‚ 19419416‚ 21868491‚ 24474082‚ 28874130‚ 29575718‚ 30274973‚ 30521064 Comment: This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 2
Pathogenic (Sep 13, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292625.15 First in ClinVar: Jul 24, 2016 Last updated: Sep 29, 2024	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24474082, 25194673, 15949004, 12132870, 21868491, 26143115, 25107687, 15655560, 12362047, 15849733, 24344984, 23752102, 15235030, 21387278, 19419416, 27300758, 26666765, 27863258, 27601186, 27978560, 28127413, 28247034, 17473388, 17569143, 9739019, 28944238, 28874130, 29575718, 30274973, 30521064, 29025352, 31159747, 24969397, 31615790, 32338768, 30787465, 35861108, 36630951, 33804961, 32522261, 31830689, 34178123, 32549215, 24362816, 12624141, 31162827, 16451135, 33422027, 38344144) (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001976052.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: research	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257170.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Number of individuals with the variant: 1
Pathogenic (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	Lynch-like syndrome Affected status: yes Allele origin: somatic	Constitutional Genetics Lab, Leon Berard Cancer Center Accession: SCV001423943.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV000592536.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021	Comment: The p.Arg711X variant has been previously reported in the literature in numerous publications in families with Lynch syndrome (selected publications: Levati 1998, Mangold 2005, Parc … (more) The p.Arg711X variant has been previously reported in the literature in numerous publications in families with Lynch syndrome (selected publications: Levati 1998, Mangold 2005, Parc 2003, Tanyi 2008). This variant leads to a premature stop codon at position 711, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of Lynch syndrome and this is the type of DNA alteration expected to cause the disorder. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001953353.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

The p.R711* pathogenic mutation (also known as c.2131C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2131. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in the germline of multiple patients with HNPCC/Lynch syndrome-associated malignancies and several of these individuals had tumors exhibiting a loss of MSH2 on immunohistochemistry (IHC) and/or microsatellite instability (Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Tang R et al. Clin Genet, 2009 Apr;75:334-45; Tanyi M et al. Eur J Surg Oncol, 2008 Dec;34:1322-7; Rios CA et al. Sao Paulo Med J, 2014;132:61-4; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Nowak JA et al. J Mol Diagn, 2017 01;19:84-91; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Ponz de Leon M et al. Scand J Gastroenterol, 2018 Jan;53:31-37; Schneider NB et al. Cancer Med, 2018 05;7:2078-2088; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781; Velázquez C et al. J Transl Med, 2020 06;18:232; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Xu Y et al. BMC Cancer, 2021 Jan;21:45). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: The MSH2 c.2131C>T (p.Arg711X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.2152C>T(p.Gln718X), c.2633_2634delA(p.Glu878fsX3), etc.). This variant is absent in 121400 control chromosomes from ExAC. In literature and clinical databases, this variant is reported as a pathogenic variant and is found in several HNPCC families/patients, including one patient with Muir-Torre Syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The MSH2 c.2131C>T; p.Arg711Ter variant (rs63750636) is reported in several individuals with Lynch syndrome and an individual with Muir-Torre syndrome (Rios 2014, Rossi 2017, Schneider 2018, see LOVD InSiGHT link). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 90903). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to InSiGHT database: https://databases.lovd.nl/shared/variants/MSH2#object_id=VariantOnTranscript%2CVariantOnGenome&id=MSH2&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00013950&search_VariantOnTranscript/DNA=c.2131C%3ET&page_size=100&page=1 Rios CA et al. Muir-Torre syndrome: case report and molecular characterization. Sao Paulo Med J. 2014;132(1):61-4. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Schneider NB et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Med. 2018 May;7(5):2078-2088.

Comment:

This is a point mutation replacing one nucleotide in the position 2131 of the MSH2 gene, leading in the replacement of Arginine with a termination stop codon in the position 711 of the MSH2 protein. This particular variant has been described in international literature in families with Lynch syndrome and with Muir-Torre syndrome (PMID: 17569143, PMID: 17473388, PMID: 16451135, PMID: 15235030). The mutation database ClinVar contains an entry for this variant (Variation ID: 90903).

Comment:

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Comment:

This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg711*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63750636, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and/or non-polyposis colorectal cancer (PMID: 12132870, 12362047, 15235030, 15849733, 16451135, 17473388, 17569143, 18289827). ClinVar contains an entry for this variant (Variation ID: 90903). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24474082, 25194673, 15949004, 12132870, 21868491, 26143115, 25107687, 15655560, 12362047, 15849733, 24344984, 23752102, 15235030, 21387278, 19419416, 27300758, 26666765, 27863258, 27601186, 27978560, 28127413, 28247034, 17473388, 17569143, 9739019, 28944238, 28874130, 29575718, 30274973, 30521064, 29025352, 31159747, 24969397, 31615790, 32338768, 30787465, 35861108, 36630951, 33804961, 32522261, 31830689, 34178123, 32549215, 24362816, 12624141, 31162827, 16451135, 33422027, 38344144)

Comment:

The p.Arg711X variant has been previously reported in the literature in numerous publications in families with Lynch syndrome (selected publications: Levati 1998, Mangold 2005, Parc 2003, Tanyi 2008). This variant leads to a premature stop codon at position 711, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of Lynch syndrome and this is the type of DNA alteration expected to cause the disorder. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic.

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
Comparison of long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis.	Xu Y	BMC cancer	2021	PMID: 33422027
A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.	Velázquez C	Journal of translational medicine	2020	PMID: 32522261
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.	Wischhusen JW	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2020	PMID: 31615790
Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome.	Georgeson P	Molecular genetics & genomic medicine	2019	PMID: 31162827
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.	Jiang W	International journal of cancer	2019	PMID: 30521064
High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer.	Bannon SA	Cancer prevention research (Philadelphia, Pa.)	2018	PMID: 30274973
Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.	Schneider NB	Cancer medicine	2018	PMID: 29575718
Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes.	Ponz de Leon M	Scandinavian journal of gastroenterology	2018	PMID: 29025352
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.	DeRycke MS	Molecular genetics & genomic medicine	2017	PMID: 28944238
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.	Rossi BM	BMC cancer	2017	PMID: 28874130
Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing.	Nowak JA	The Journal of molecular diagnostics : JMD	2017	PMID: 27863258
Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.	Carneiro da Silva F	PloS one	2015	PMID: 26437257
Muir-Torre syndrome: case report and molecular characterization.	Rios CA	Sao Paulo medical journal = Revista paulista de medicina	2014	PMID: 24474082
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer.	Pérez-Carbonell L	Gut	2012	PMID: 21868491
Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome.	Bozzao C	Cancer	2011	PMID: 21387278
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.	Tang R	Clinical genetics	2009	PMID: 19419416
Difficulties in recognizing families with Hereditary Non-polyposis Colorectal Carcinoma. Presentation of 4 families with proven mutation.	Tanyi M	European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology	2008	PMID: 18289827
Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.	Papp J	World journal of gastroenterology	2007	PMID: 17569143
A mononucleotide markers panel to identify hMLH1/hMSH2 germline mutations.	Pedroni M	Disease markers	2007	PMID: 17473388
Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.	Lagerstedt Robinson K	Journal of the National Cancer Institute	2007	PMID: 17312306
Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).	Kurzawski G	Clinical genetics	2006	PMID: 16451135
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.	Mangold E	International journal of cancer	2005	PMID: 15849733
hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients.	Apessos A	British journal of cancer	2005	PMID: 15655560
A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.	Mangold E	Journal of medical genetics	2004	PMID: 15235030
Cancer risk in 348 French MSH2 or MLH1 gene carriers.	Parc Y	Journal of medical genetics	2003	PMID: 12624141
Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States.	Kurzawski G	Journal of medical genetics	2002	PMID: 12362047
hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer.	Kim JC	Cancer detection and prevention	2001	PMID: 12132870
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.2131C%3ET	-	-	-	-
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Text-mined citations for rs63750636 ...

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Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000251.3(MSH2):c.2131C>T (p.Arg711Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750636 ...