2-47476492-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000251.3(MSH2):c.2131C>T(p.Arg711Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R711R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:24U:1

Conservation

PhyloP100: 3.72

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-47476492-C-T is Pathogenic according to our data. Variant chr2-47476492-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90903.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476492-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2131C>T	p.Arg711Ter	stop_gained	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2131C>T	p.Arg711Ter	stop_gained	13/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000224

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2022	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, 32522261, 31830689, 34178123, 32549215) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 23, 2020	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. -

Lynch syndrome 1

Pathogenic:5Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 07, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 11, 2021	PVS1, PS4, PP5. -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Oct 24, 2022	ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2021	- -

Lynch syndrome

Pathogenic:5

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing premature termination codon -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2017	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. -
Pathogenic, criteria provided, single submitter	research	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	Jan 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 05, 2024	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. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2021	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. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 30, 2019

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. -

Lynch-like syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

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. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

A;A;A

Vest4

0.96

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over