NM_000251.3(MSH2):c.2131C>T (p.Arg711Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 29, 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:: RCV000129341.12

Allele description [Variation Report for NM_000251.3(MSH2):c.2131C>T (p.Arg711Ter)]

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

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.2131C>T (p.Arg711Ter)

HGVS:

NC_000002.12:g.47476492C>T
NG_007110.2:g.78369C>T
NM_000251.3:c.2131C>TMANE SELECT
NM_001258281.1:c.1933C>T
NP_000242.1:p.Arg711Ter
NP_000242.1:p.Arg711Ter
NP_001245210.1:p.Arg645Ter
LRG_218t1:c.2131C>T
LRG_218:g.78369C>T
LRG_218p1:p.Arg711Ter
NC_000002.11:g.47703631C>T
NM_000251.1:c.2131C>T
NM_000251.2:c.2131C>T
p.Arg711*
p.Arg711X
p.R711*

Protein change:

R645*

Links:

dbSNP: rs63750636

NCBI 1000 Genomes Browser:

rs63750636

Molecular consequence:

NM_000251.3:c.2131C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.1933C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184105	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 23, 2021)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 12362047, 12624141, 15235030, 15655560, 15849733, 17312306, 17569143, 18289827, 19419416, 24474082, 26437257, 27863258, 28874130, 28944238, 29025352, 29575718, 30274973, 30521064, 31162827, 31615790, 32338768, 32522261, 33422027 Citation Link,
SCV000685015	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 15235030, 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 21868491, 24474082, 28874130, 29575718, 30274973, 30521064, 25741868
SCV000821737	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184105

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 23, 2021)

germline

clinical testing

PubMed (23)
[See all records that cite these PMIDs]

Citation Link,

SCV000685015

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 29, 2023)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV000821737

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States.

Kurzawski G, Suchy J, Kładny J, Safranow K, Jakubowska A, Elsakov P, Kucinskas V, Gardovski J, Irmejs A, Sibul H, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Clark J, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, et al.

J Med Genet. 2002 Oct;39(10):E65. No abstract available.

PubMed [citation]

PMID:: 12362047
PMCID:: PMC1734972

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

See all PubMed Citations (26)

Details of each submission

From Ambry Genetics, SCV000184105.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (23)

Description

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.

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

From Color Diagnostics, LLC DBA Color Health, SCV000685015.4

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

Description

This variant 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.

#	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		not provided	not provided	not provided	not provided

From GeneKor MSA, SCV000821737.2

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

Description

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).

#	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: Apr 20, 2024

ClinVar

Relating variation to medicine