NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jun 7, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000202008.17

Allele description

NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)

Other names:

p.R389*:CGA>TGA

HGVS:

NC_000002.12:g.47429830C>T
NG_007110.2:g.31707C>T
NM_000251.3:c.1165C>TMANE SELECT
NM_001258281.1:c.967C>T
NP_000242.1:p.Arg389Ter
NP_000242.1:p.Arg389Ter
NP_001245210.1:p.Arg323Ter
LRG_218t1:c.1165C>T
LRG_218:g.31707C>T
LRG_218p1:p.Arg389Ter
NC_000002.11:g.47656969C>T
NM_000251.1:c.1165C>T
NM_000251.2:c.1165C>T
NM_000251.3:c.1165C>T
p.Arg389*
p.Arg389Stop
p.R389*

Protein change:

R323*

Links:

dbSNP: rs587779075

NCBI 1000 Genomes Browser:

rs587779075

Molecular consequence:

NM_000251.3:c.1165C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149403	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 25, 2023)	germline	clinical testing	Citation Link,
SCV000257124	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15235030, 21642682, 22883484, 25430799, 25648859, 25117503, 25741868
SCV000601425	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 7, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 26681312, 25648859, 25569433, 25430799, 15235030, 22883484, 25117503, 15849733, 19459153, 15855432, 15713769, 31054147, 33471991, 26467025
SCV002036646	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002037401	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, et al.

JAMA. 2011 Jun 8;305(22):2304-10. doi: 10.1001/jama.2011.743.

PubMed [citation]

PMID:: 21642682

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (16)

Details of each submission

From GeneDx, SCV000149403.17

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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; Observed in individuals with personal and family histories consistent with pathogenic variants in this gene (Beck et al., 1997; Millar et al., 1999; Mangold et al., 2004; Choi et al., 2009; Chong et al., 2009; Bonadona et al., 2011; Chubb et al., 2015); 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: 15235030, 25569433, 17453009, 9052445, 25117503, 22883484, 20215533, 10196371, 25525159, 25430799, 26681312, 25559809, 12658575, 27863258, 15849733, 27601186, 25648859, 28874130, 19459153, 19698169, 11920650, 15713769, 21642682, 18566915, 30521064, 29933315, 31054147, 31857677, 31921681, 32489267, 32294063, 31615790, 31332305, 31742824, 34178123, 34148862, 31830689, 36073783)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257124.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (7)

Description

PVS1, PM2, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601425.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This variant causes the premature termination of MSH2 protein synthesis. In the published literature, this variant has been reported in individuals with Lynch syndrome associated cancers (PMID: 15235030 (2004), 15849733 (2005), 15855432 (2005), 15713769 (2005), 19459153 (2009), 22883484 (2013), 25117503 (2014), 26681312 (2015), 25648859 (2015), 25430799 (2015), 31054147 (2019)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036646.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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