NM_000251.3(MSH2):c.181C>T (p.Gln61Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 24, 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:: RCV000202086.9

Allele description [Variation Report for NM_000251.3(MSH2):c.181C>T (p.Gln61Ter)]

NM_000251.3(MSH2):c.181C>T (p.Gln61Ter)

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.181C>T (p.Gln61Ter)

HGVS:

NC_000002.12:g.47403372C>T
NG_007110.2:g.5249C>T
NM_000251.3:c.181C>TMANE SELECT
NM_001258281.1:c.-18C>T
NP_000242.1:p.Gln61Ter
NP_000242.1:p.Gln61Ter
LRG_218t1:c.181C>T
LRG_218:g.5249C>T
LRG_218p1:p.Gln61Ter
NC_000002.11:g.47630511C>T
NM_000251.1:c.181C>T
NM_000251.2:c.181C>T

Protein change:

Q61*

Links:

dbSNP: rs63750951

NCBI 1000 Genomes Browser:

rs63750951

Molecular consequence:

NM_001258281.1:c.-18C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000251.3:c.181C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000257153	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	research
SCV000567927	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Aug 1, 2018)	germline	clinical testing	Citation Link,
SCV001953610	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
SCV001973758	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV004220961	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 24, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 21642682, 12660027, 20587412, 22208277, 24344984, 27064304, 28152038, 28514183, 28765196, 29345684, 30918532, 31054147, 31844177, 32453797, 32540221, 26467025

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	unknown	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research

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

Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.

Sarroca C, Peltomäki P, Alfano N, Tedesco G, Della Valle A, Dominguez A, Lynch HT.

Cancer Genet Cytogenet. 2003 Apr 1;142(1):13-20.

PubMed [citation]

PMID:: 12660027

See all PubMed Citations (16)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257153.1

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000567927.3

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

Description

This pathogenic variant is denoted MSH2 c.181C>T at the cDNA level and p.Gln61Ter (Q61X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals and families with Lynch syndrome (Sarroca 2003, Sjursen 2010, Bonadona 2011). We consider MSH2 Gln61Ter to be pathogenic.

#	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, SCV001953610.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973758.1

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The MSH2 c.181C>T (p.Gln61*) variant causes the premature termination of MSH2 protein synthesis. This variant has been reported in the published literature in affected individuals with colorectal cancer (PMID: 20587412 (2010)), Lynch Syndrome (PMIDs: 21642682 (2011) and 27064304 (2016)), as well as in an individual with both colorectal and bladder cancer (PMID: 29345684 (2018)). The frequency of this variant in the general population, 0.000057 (1/17498 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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

Last Updated: May 7, 2024

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